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Thiazoles, Their Benzofused Systems, and Thiazolidinone Derivatives: Versatile and Promising Tools to Combat Antibiotic Resistance

  • Stella Cascioferro
    Stella Cascioferro
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
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    Orcidhttp://orcid.org/0000-0002-4725-1881
  • , 
  • Barbara Parrino
    Barbara Parrino
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
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  • Daniela Carbone
    Daniela Carbone
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
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  • Domenico Schillaci
    Domenico Schillaci
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
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  • Elisa Giovannetti
    Elisa Giovannetti
    Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, DeBoelelaan 1117, 1081HV, Amsterdam, The Netherlands
    Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, via Giovannini 13, 56017 San Giuliano Terme, Pisa, Italy
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  • Girolamo Cirrincione
    Girolamo Cirrincione
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
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  • Patrizia Diana*
    Patrizia Diana
    Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
    *Phone: 0039-09123896815. Email: [email protected]
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    Orcidhttp://orcid.org/0000-0002-4883-2004
Cite this: J. Med. Chem. 2020, 63, 15, 7923–7956
Publication Date (Web):March 25, 2020
https://doi.org/10.1021/acs.jmedchem.9b01245

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Abstract

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Thiazoles, their benzofused systems, and thiazolidinone derivatives are widely recognized as nuclei of great value for obtaining molecules with various biological activities, including analgesic, anti-inflammatory, anti-HIV, antidiabetic, antitumor, and antimicrobial. In particular, in the past decade, many compounds bearing these heterocycles have been studied for their promising antibacterial properties due to their action on different microbial targets. Here we assess the recent development of this class of compounds to address mechanisms underlying antibiotic resistance at both bacterial-cell and community levels (biofilms). We also explore the SAR and the prospective clinical application of thiazole and its benzofused derivatives, which act as inhibitors of mechanisms underlying antibiotic resistance in the treatment of severe drug-resistant infections. In addition, we examined all bacterial targets involved in their antimicrobial activity reporting, when described, their spontaneous frequencies of resistance.

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1. Introduction

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Antibiotic resistance (AMR) is among the most relevant health problems of this century. At least 700 000 people die of no longer treatable infections every year in the world. (1)
AMR crisis involves any class of antibiotic including the second- and third-line antibiotics once considered the last resort drugs to tackle common infections. We are losing our ability to keep under control many common infections; consequently, one of the pillars on which modern medicine is based threatens to collapse.
The phenomenon of AMR at biochemical and physiological levels may manifest in any single bacterial cell (planktonic growth) or in a sessile complex microbial community (biofilm). (2) Bacteria might become resistant to antibiotics at the cellular level, and bacteria can become resistant to antibiotics by inactivating or altering the molecular structure of an antibiotic, modifying the antibiotic target, and decreasing the intracellular drug concentration by expressing efflux pumps. These biochemical mechanisms are present in any single bacterial cell embedded in the biofilm structure too, however, a set of adaptive and intrinsic mechanisms due to growth as a community contribute to making biofilms up to a thousand times more resistant than single bacterial cells. (3)
Within a global strategy for fighting antibiotic resistance, in 2005, the World Health Organization (WHO) published for the first time a list called Critical Important Antimicrobials (CIA). This list includes antibiotics and antimicrobials widely used in the world, divided in three categories of clinical importance (critically important, divided in highest priority and high priority; highly important; important) with the scope of preserving the clinical use and the rational employment of these molecules. A recent recommendation of the Interagency Coordination Group on Antimicrobial Resistance (IACG) of the United Nations is to stop the use of antibiotics categorized as the highest priority critically (i.e., third and higher generation cephalosporins, macrolide, quinolones and fluoroquinolones, glycopeptides, macrolides and ketolides, polymyxins) in nonclinical settings (farms, food, and feed production). (4)
There are indeed many scientists who fear that the world is going toward a “post-antibiotic era” where common infections, which were easily cured, could become chronic or fatal. As a consequence, about 10 million deaths caused by infectious diseases treatment failure could be reached in 2050. (5)
In this scenario, the development of new small molecules able to counteract the commonest mechanisms underlying antibiotic resistance including enzymatic inactivation of antibiotics, alterations in cell penetrability, efflux pumps activity or biofilm formation is urgently required. (6,7)
Many heterocyclic compounds have been synthesized in the past decade in the attempt to obtain new antimicrobials, which would be able to treat infections caused by resistant bacterial strains. Herein we focused on synthetic molecules bearing the thiazole, benzothiazole, and thiazolidinone scaffolds, which are widely recognized as nuclei of great value for obtaining molecules endowed with various biological activities, (8) including analgesic, (9) anti-inflammatory, (9) antidiabetic, (10) antitumor, (11) and antimicrobial. (12)
Sulfur containing compounds such as thiazole, compared to other five-membered heterocycles such as oxazole and imidazole, possess unique features due to the low lying C–S σ* orbitals that, conferring small regions of low electron density on sulfur (σ-holes), may play a role in drug–target interactions. (13) The presence of sulfur exerts also significant effect on bond angles and the topology of substituents, it being associated with longer lengths and smaller bond angles. Moreover, thiazole ring systemshows cLogP and cLogD values near to 0.5 and pKa and pKBHX (the latter related to the H-bond interaction properties) of 2.53 and 1.37, respectively. Although the benzo-fusion of thiazoles causes a significant reduction of pKa values, this modification has a limited effect on pKBHX values (Table 1). (14)
Table 1. Chemical-Physical Properties of Thiazole, Imidazole, and Oxazole Scaffolds
In particular, we assess the recent development (2008–2019) of this class of compounds in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also review the SAR and the potential clinical implementation of thiazole and benzothiazole with antibacterial properties in the therapies for severe drug-resistant infections.

2. DNA Gyrase and Topoisomerase IV Inhibitors

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To obtain more potent therapeutic strategies, many targets were investigated, among them, type II topoisomerase enzymes, which include bacterial DNA gyrase and topoisomerase IV. These enzymes were discovered in 1976 in the Gram-negative pathogen Escherichia coli by Gellert and co-workers and are at the center of many studies because of their commercial success with the development of the fluoroquinolones. (15) Gyrase maintains negative supercoiling of the bacterial chromosome, while topoisomerase IV is responsible for untangling daughter chromosomes. Type II topoisomerases are crucial enzymes for maintaining DNA integrity during the replication playing key roles in DNA replication, transcription, and repair, recombination, and transposition. (16) One of the most important advantage to consider the bacterial type II topoisomerases as targets for the design of novel therapeutic classes of antibiotics is that they are highly conserved enzymes in bacterial strains and therefore their inhibition could lead to a broad spectrum activity. (17)
Fluoroquinolones represent an important class of dual inhibitors of bacterial type II topoisomerases. Despite their clinical success in the past, their use is now limited by growing antibiotic resistance, which strongly compromised their effectiveness. Both for DNA gyrase and topoisomerase IV, fluoroquinolones, interacting with the enzyme-bound DNA complex, determine conformational modifications preventing the assembly of DNA strands that impede the normal enzyme activity. This causes the inhibition of DNA synthesis and the consequent death of the bacterial cell.
Several searches have been carried out in order to obtain new drugs able to inhibit both enzymes, DNA gyrase and topoisomerase IV, reducing the probability that bacteria develop antibiotic resistance mechanisms. (18) A special effort must be made in identifying selective inhibitors toward the bacterial form which are inactive against the eukaryotic type II topoisomerases. This desirable selectivity can be achieved because there are distinct structural differences from the homodimeric mammalian enzyme counterparts.
Structurally, DNA gyrase is composed of two heterodimeric subunits GyrA and two GyrB in complex, whereas topoisomerase IV consists of two ParC and two ParE subunits.
With the aim of obtaining specific inhibitors of GyrB, which is considered an interesting target to overcome the cross-resistance to quinolones, Ronkin and collaborators performed a high-throughput screen. This screen identified compound 1 (Table 2), which showed an inhibitory activity against GyrB in E. coli with a Ki value of 2.9 μM. (19,20) The X-ray crystal structure of this derivative inside the GyrB active site of Staphylococcus aureus allowed the identification of structural features responsible for the interactions with the enzyme, guiding the synthesis of the analogues (1a–d and 2a–y). It was observed that (i) the pyrazole moiety was involved in a hydrogen bond with Asp81 and a highly conserved structural water molecule. (ii) the presence in position 2 of the thiazole ring of a 3-pyridyl moiety (2e), assuring an additional hydrogen bond with Arg136, improved the activity by 5–10-fold compared to 1a and 1d (Figure 1), (iii) the substituent at the 4 position of the thiazole ring affected the activity of the compound, substituents larger than methyl should be tolerated and lipophilic groups gave better results, (iv) the position 5 of the pyrazole ring can be substituted with carboethoxy, amide, or carbamate groups. In particular, the ethyl amide compounds are twice as potent as the corresponding ethyl esters. Another key feature is the presence of a carbamate group, which was able to form an additional hydrogen bond with Asn46, as observed in derivatives 2t–y (Table 2), which were the most potent in term of enzymatic inhibition showing Ki values in the range 0.040–3.4 μM. Despite their interesting activity against GyrB, carbamates 2t–y did not show antibacterial activity against wild-type Escherichia coli strains as well as S. aureus ATCC 29213 and Streptococcus pneumoniae ATCC 10015; this is probably due to the efflux pumps antimicrobial resistance mechanism.
Table 2. Chemical Structures and E. coli GyrB Inhibitory Activity of Compounds 1, 1a–d, and 2a–y

Figure 1

Figure 1. Schematic representation of the binding mode in GyrB active site of S. aureus of compound 2e. Hydrogen bonds are represented as blue dashed line.

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In an attempt to discover innovative inhibitors of both GyrB and ParE, Stokes and collaborators synthesized two benzothiazole ethyl urea compounds 3a,b (Figure 2), which potently inhibited in vitro the ATPase activity of E. coli DNA gyrase and topoisomerase IV, eliciting IC50s in the range from 0.0033 to 0.046 μg/mL. (21) Derivatives 3a,b were extremely more potent against topoisomerase enzymes than the reference drug novobiocin. Moreover, differently from compounds 1 and 2, they showed a significant antibacterial activity against a broad range of Gram-positive/negative pathogens with MIC values of 0.008, 0.03, and 0.06 μg/mL against S. pneumoniae ATCC 49619, Staphylococcus epidermidis ATCC 1228, and Streptococcus pyogenes ATCC 51339, respectively.

Figure 2

Figure 2. Chemical structures of compounds 3a,b, 4, 5, and chlorobiocin (6).

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Compounds 3a,b were also tested for evaluating their spontaneous frequencies of resistance (FoRs). It is known that antibacterial compounds acting on a single bacterial target show FoRs in the range 10–6 to 10–9, (22) conversely, the FoR values for the two benzothiazole ethyl urea derivatives 3a,b against S. aureus ATCC 29213 were <2.3 × 10–10 and <2.3 × 10–11, respectively, at concentrations 8-fold the MIC. This behavior seems to be due to the capability of the compounds 3a,b of simultaneously inhibiting two intracellular targets, i.e., GyrB and ParE. Additionally, these compounds proved to be not toxic when assayed against the HepG2 human liver cell line.
It was observed that the presence of a cyclic amine between the carboxylate and the C-5 aryl group enhanced the antibacterial activity and the solubility compared to the derivatives without this group. (23) Further improvement in the PK profile was obtained with the inclusion of an α substituent to the carboxylic acid, which showed enhanced solubility, excellent oral bioavailability, and lower clearance. Remarkably, compounds 3a,b had powerful inhibitory activity against S. aureus topoisomerase IV (0.012 and 0.008 μg/mL, respectively), proving their selectivity toward the bacterial isoform without affecting human topoisomerase II.
Most of the known bacterial topoisomerase inhibitors have been identified with the aid of computational techniques such as virtual screenings and docking studies in the active sites. (24)
Brvar and collaborators employed the crystal structure of the N-terminal portion of the B subunit of DNA gyrase, the G24 protein (PDB 1KZN), cocrystallized with the natural inhibitor, chlorobiocin (6) (Figure 2) to generate a structure-based pharmacophore model. (25) Twelve features involved in the interaction between the inhibitor and the enzyme were identified: (i) the presence of two hydrogen bond donors, (ii) two hydrogen bond acceptors, (iii) an aromatic ring, and (iv) seven hydrophobic portions. This pharmacophore was successfully validated by assessing its ability to recognize the bioactive conformation of 6, and then was used to perform a large scale virtual screening of 5 million compounds, which allowed the identification of 400 new hit compounds belonging to different classes.
Further in silico studies, including a docking calculation for the potential interactions of the G24 active-site with the binding site for ATP, resulted in the identification of new strong antigyrase agents with 4,5′-bithiazole-2,2′-diamine structure. Among these agents, compound 4 (Figure 2) had the most promising DNA gyrase inhibitory activity displaying an IC50 of 5.5 μM.
Subsequently, a commercially available library of 240 4′-methyl-N2-phenyl-[4,5′-bithiazole]-2,2′-diamines was docked into the G24 ATP-binding site, using the software GOLD. This study focused on compounds capable to bind the previously selected residues Asp73, Thr165 through W1001 water molecule and Arg136. Eight compounds were selected to be examined for their inhibitory activity on DNA gyrase inhibitory activity, and the bithiazole 5 (Figure 2) emerged for its potency, showing an IC50 of 1.1 μM. The binding mode of this derivative was confirmed by X-ray crystallography (Figure 3), and its structure has been reported in the RCSB Protein Data Bank (PDB 4DUH). (25) Despite their structural diversity, compound 5 and the coumarin inhibitor chlorobiocin (6) showed a very similar binding pattern. As observed for 6, the bithiazole 5 formed two hydrogen bonds with (1) Asp73, through the 2′-propionylamido group, which was oriented in the active site as the 5-methylpyrrole ring of 6, and (2) the conserved water molecules that were coordinated with the residues Asp73, Gly77, and Thr165. The propionyl moiety participated also to the hydrophobic interactions with the binding pocket made by Val43, Val71, Val120, and Val 167. This is the same binding pocket, occupied by the methylpyrrole group of 6. Additionally, the second thiazole ring was oriented in a manner analogous to the methyl groups of the sugar part of 6 and formed hydrophobic interactions with the residues Ile78, Ile90, and Val120. The 2-aminothiazole moiety seems essential in the DNA gyrase inhibition as it contains an acceptor–donor interaction pattern, which is a fundamental requirement for this activity. Similarly, the presence of a hydrogen bond acceptor on the para position of the phenyl ring seems to play a key role in the enzymatic activity.

Figure 3

Figure 3. (A) Bithiazole 5 in G24 active site. Hydrogen bonds are designed as dotted lines; electronic density, contoured at 2σ, is reported as meshed net. (B) Chlorobiocin (6) binding mode into the G24 ATP-binding. (25)Reproduced with permission from ref (25). Copyright 2012 American Chemical Society.

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An important class of gyrase inhibitors is constituted by marine alkaloids, which are widely recognized as molecules of great value in terms of biological properties and many derivatives in the past decade have been successfully developed for different therapeutic purposes. (26−28)
However, the marine alkaloids oroidin analogues have attracted great attention for their significant antibacterial and antibiofilm activities. (29−32)
Performing a virtual screening of a library of oroidin analogues employing the E. coli GyrB crystal structure (PDB 4DUH), Tomǎsič and co-workers identified a 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole derivative 7a (Table 3) able to inhibit E. coli DNA gyrase with an IC50 of 12 μM. (33) To better understand how to optimize the structure of the compound 7a in order to obtain more potent inhibitors, its binding mode in the ATP-binding site of E. coli GyrB (PDB 4DUH) was investigated. The 4,5-dibromo-1H-pyrrole-2-carboxamide moiety is involved in the interaction with the hydrophobic pocket and is able to make hydrogen bonds with the Asp73 side chain as well as with the conserved water molecule, miming ATP interactions with the same residue, whereas the position of the 2-amino group on the thiazole ring allows substitution with functional groups, such as oxalyl, malonyl, and succinyl (Figure 4), for interaction with Arg76 and/or Arg136.
Table 3. Inhibitory Activity of E. coli and S. aureus DNA Gyrase and Topoisomerase IV by the 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles Containing the 4,5-Dibromo-1H-pyrrole (7a–h), 4,5-Dichloro-1H-pyrrole Moiety (7i–n), or 1H-Indole Moiety (7o–s)
          DNA gyrase IC50 (Kda) [μM] or RA [%]b topoisomerase IV IC50 (Kda) [μM] or RA [%]b E. coli MIC [μg/mL]
compd * R X n E. coli S. aureus E. coli S. aureus wt tolC impA
negc         100% 100% 100% 100%      
NBd         0.17 μM 0.040 μM 11 μM 27 μM      
7a S       12 μM 90% 101% 102% >256 64 64
7b R       47 μM 118% 96% 92% >256 64 64
7c S OC2H5 Br 0 0.10 μM 80 μM 74% 180 μM >256 128 >256
7d S OCH3 Br 1 0.096 μM 110 μM 86 μM 74% >256 16 32
7e S OCH3 Br 2 0.093 μM 113% 97% 99% >256 32 64
7f S OH Br 0 0.058 μM 120 μM 200 μM 78 μM >256 256 >256
7g S OH Br 1 0.069 μM 86 μM 74 μM 76 μM >256 256 >256
7h S OH Br 2 0.049 μM 270 μM 90% 110 μM >256 256 >256
7i   OC2H5 Cl 0 0.40 μM 320 μM 300 μM 290 μM >256 256 >256
7j   OCH3 Cl 1 0.40 μM 63% 97% 101% >256 32 32
7k   OCH3 Cl 2 0.89 μM 86% 100% 93% >256 >256 >256
7l   OH Cl 0 0.59 μM 300 μM 82% 170 μM >256 >256 >256
7m   OH Cl 1 0.13 μM 87% 98% 102% >256 >256 >256
7n   OH Cl 2 0.30 μM 10 μM 72% 97% >256 >256 >256
7o   OC2H5   0 10 μM 76% 101% 99% nt nt nt
7p   OCH3   2 9.1 μM 87% 101% 104% nt nt nt
7q   OH   0 7.7 μM 79% 47% 99% >256 >256 128
7r   OH   1 7.6 μM 117% 96% 103% >256 >256 >256
7s   OH   2 8.1 μM 95% 99% 79% >256 >256 >256
a

K determined by surface plasmon resonance.

b

Residual activity of the enzyme at 100 μM concentration of the tested compound. nt: not tested.

Figure 4

Figure 4. Schematic representation of the binding mode in the E. coli GyrB ATP-binding site of ATP and compound 7a. Hydrogen bonds are represented as green arrows.

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Many analogues were prepared to get more insights into the SAR of the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole class, as well as to improve the affinity toward the enzyme. These studies also evaluated the effect of the replacement of the 4,5-dibromo-1H-pyrrole with the 4,5-dichloro-1H-pyrrole or 1H-indole moieties. In addition, experiments with the (R)-isomer (7b) of compound 7a assessed the influence of chirality on enzymatic inhibition.
All the synthesized compounds were tested against E. coli DNA gyrase. Then the compounds with IC50s lower than 50 μM were evaluated for their inhibitory activities against S. aureus DNA gyrase as well as E. coli and S. aureus topoisomerases IV (Table 3).
The substituents on the pyrrole ring play a pivotal role in the activity of these compounds. This might be explained by the hydrophobic interactions of the bromine atoms with the pocket of the ATP-binding site. The introduction of an oxalyl, malonyl, or succinyl group, as a hydrogen bond acceptor, led to derivatives (7c,d,e), as suggested by computational studies. These compounds enhanced the inhibition of E. coli DNA gyrase, with IC50s of 0.10, 0.096, and 0.093 μM, respectively, probably due to their capacity to interact with Arg136. The stereochemistry seems also to have an important role in determining activity (S-isomers, in fact, showed stronger inhibitory activity than the (R)-counterparts.
In the indole series (compounds 7o–s), the activity was maintained in the low micromolar range. Conversely, the substitution of the bromine with chlorine atoms on the pyrrole ring (compounds 7i–n) led to a decrease inpotency toward DNA gyrase as well as topoisomerase IV.
Unfortunately, despite the activity showed by compounds 7 in the enzymatic assay, no derivative of the series showed antibacterial activity at the concentration of 50 μM against the Gram-negative E. coli ATCC 25922, P. aeruginosa ATCC 27853, and the Gram-positive E. faecalis ATCC 29212 and S. aureus ATCC 25923 bacterial strains. Only compounds 7d against E. faecalis and 7e and 7j against S. aureus displayed percentages of growth inhibition higher than 50%.
To investigate if the lack of antibacterial effects against the Gram-negative pathogens of this class was ascribable to permeability problems or to efflux pumps, the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles 7 were tested against permeabilized (impA) and efflux pump knockout (ΔtolC) strains of E. coli. However, among the tested compounds, only five derivatives, 7a, 7b, 7d, 7e, and 7j, showed better antibacterial effects toward impA and ΔtolCE. coli strains than the wild-type.
Even if DNA gyrase is a fundamental enzyme for the bacterial viability, often it was observed that its inhibition in a biochemical assay does not correspond to an antibacterial effect at the cellular level.
Structural modifications of the most active E. coli DNA gyrase inhibitor 7f, which showed an IC50 value of 58 nM, led to two series of nanomolar inhibitors 8a–e (Table 4) and 9a–g (Table 5). (34,35) In particular, the replacement of the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffold with a planar benzothiazole-2,6-diamine moiety and the move of the 4,5-dibromopyrrole-2-carbonyl group from N-6 to N-2 of the central core proved to be advantageous for the enzymatic activity. The most potent inhibitor was the derivative 8d, which displayed an IC50 of 38 nM (Table 4). However, even if the DNA gyrase inhibitory activity increased, no improvement in the antibacterial properties was observed, probably because efflux pumps inactivated these compounds. The compounds, in fact, proved to be significantly more potent toward the efflux deficient strain, ΔtolCE. coli than the wild type.
Table 4. Inhibition of E. coli and S. aureus DNA Gyrase and Topoisomerase IV by the Benzothiazole Compounds with the Pyrrole-2-carboxamido Moiety at Position 6 on the Benzothiazole Core (8a–e)
      DNA gyrase IC50 [μM] topoisomerase IV IC50 [μM]
compd n R E. coli S. aureus E. coli S. aureus
novobiocin     0.17 0.040 11 27
8a 0 CH2CH3 0.081 ± 0.05 >100 >100 >100
8b 1 CH3 0.24 ± 0.02 >100 >100 >100
8c 2 CH3 0.87 ± 0.21 >100 >100 >100
8d 0 H 0.038 ± 0.001 >100 5.4 ± 1.0 2.5 ± 0.2
8e 2 H 0.057 ± 0.018 >100 4.5 ± 0.7 2.2 ± 0.3
Table 5. Inhibition of E. coli and S. aureus DNA Gyrase and Topoisomerase IV by the Benzothiazole Compounds with the Pyrrole-2-carboxamido Moiety at Position 2 on the Benzothiazole Core (9a–g)
For the compounds of the series 9, the highest activity was reached against the E. coli DNA gyrase by the derivative 9d, which showed an IC50 value against this enzyme of 33 nM (Table 5).
Taking into account the interesting antibacterial properties described for benzothiazole and thiazolidinone scaffolds, Haroun and collaborators synthesized a new series of compounds 10a–l (Table 6), bearing both bioactive nuclei. All compounds were tested for their activity against the Gram-negative E. coli (ATCC 35210), Enterobacter cloacae, Pseudomonas aeruginosa (ATCC 27853), Salmonella typhimurium (ATCC 13311) pathogens, as well as against the Gram-positive Listeria monocytogenes (NCTC 7973), Bacillus cereus (clinical isolate), Micrococcus flavus (ATCC 10240), and S. aureus (ATCC 6538). All of these novel derivatives showed good antibacterial potency, proving to be more active than reference drugs, such as ampicillin and streptomycin, with MIC values in the range of 0.0018–0.28 μmol/mL and MBC values in the range of 0.0036–0.37 μmol/mL. An initial hypothesis on the mode of action of these compounds came from an evaluation of docking studies conducted on topoisomerase II DNA gyrase (1KZN) and E. coli Mur B (2Q85) (Figure 5A,B), showing that these compounds were capable of binding to the active sites of both enzymes, with a specific affinity toward MurB. In particular, the best binding score and binding energy values toward both enzymes were found for compound 10a, which interacted with the binding site of topoisomerase II DNA gyrase through two hydrogen bonds, between the nitrogen atom of the central chain and the Thr165 and between the keto group of thiazolidinone ring and Asn46. Moreover, the phenyl ring is involved in hydrophobic interactions with Val71, Val167, Ala47, and Val43. The greater affinity toward MurB observed for derivative 10a was due to the ability of this compound to form four hydrogen bonds with the active site, two with Gly123, and the other two with Arg124 and Tyr190. In addition, the benzothiazole scaffold formed hydrophobic interactions with Val129, Leu218, and Ala124. MurB is a UDP-N-acetylenolpyruvoylglucosamine reductase, which leads the catalysis the second committed reaction in the biosynthesis of peptidoglycan, and therefore it is fundamental for bacterial growth. However, assays on the enzyme were not conducted to confirm the computationally obtained data, therefore the target of this series remains unknown. Additionally, it should be useful to investigate the potential of compounds 10a–l as pan assay interference compounds (PAINS), because many subclasses of aminothiazoles were classified in this category and, therefore, could give false positive results. (36)
Table 6. Chemical Structures and Antibacterial Activity of Compounds 10a–l
    MIC values (MBC values) μmol/mL × 102
compd R B. cereus M. flavus S. aureus L. monocytogenes E. coli E. cloacae P. aeruginosa S. typhimurium
10a H 1.49 (2.97) 2.97 (5.94) 1.19 (1.49) 1.49 (2.97) 0.23 (2.97) 1.49 (2.97) 4.45 (5.94) 1.49 (2.97)
10b 4-OH 4.90 (9.80) 9.80 (19.6) 4.90 (9.80) 4.90 (9.8) 9.80 (19.6) 4.90 (9.80) 4.90 (9.80) 4.90 (9.80)
10c 4-OCH3 4.80 (19.2) 9.60 (19.2) 4.80 (9.60) 9.60 (19.2) 14.4 (19.2) 7.20 (9.60) 9.60 (19.2) 4.80 (9.60)
10d 4-OH; 3-OCH3 4.60 (9.20) 13.9 (18.6) 9.20 (37.3) 18.6 (37.3) 13.9 (18.6) 6.90 (9.20) 9.20 (37.3) 3.45 (4.60)
10e 2-Cl 4.80 (9.60) 9.60 (19.2) 4.80 (9.60) 9.60 (19.2) 9.60 (19.2) 4.80 (9.60) 9.60 (19.2) 4.80 (9.60)
10f 3-Cl 4.60 (9.20) 4.60 (9.20) 4.60 (9.20) 4.60 (9.20) 0.18 (0.36) 4.60 (9.20) 4.60 (9.20) 4.60 (9.20)
10g 4-Cl 4.80 (19.2) 9.60 (19.2) 4.80 (9.60) 9.60 (19.2) 9.60 (19.2) 4.80 (9.60) 9.60 (19.2) 2.40 (4.80)
10h 2-NO2 9.10 (18.2) 9.10 (18.2) 9.10 (18.2) 4.50 (9.10) 9.10 (18.2) 4.50 (9.10) 4.50 (9.10) 9.10 (18.2)
10i 3-NO2 14.0 (18.4) 18.4 (36.8) 14.0 (18.4) 18.4 (36.8) 23.3 (36.8) 23.3 (36.8) 18.4 (36.8) 4.60 (9.20)
10j 4-NO2 0.58 (1.16) 9.20 (18.4) 0.58 (1.16) 9.20 (18.4) 9.20 (18.4) 2.30 (9.20) 9.20 (18.4) 0.58 (1.16)
10k 4-OH; 3,5-OCH3 8.80 (17.6) 8.80 (17.6) 4.40 (8.80) 2.20 (8.80) 8.80 (17.6) 4.40 (8.80) 2.20 (8.80) 2.20 (8.80)
10l 4-OH; 3-OCH3; 5-I 7.20 (28.8) 7.20 (14.4) 3.60 (7.20) 28.8 (36.0) 7.20 (14.4) 3.60 (14.4) 14.4 (28.8) 7.20 (14.4)

Figure 5

Figure 5. Binding mode of compound 10a in the topoisomerase II DNA gyrase active site (1KZN) (A) and binding mode of compound 10a in the E. coli Mur B active site (2Q85) (B). Yellow, van der Waals interactions; blue dashed line, hydrogen bond; blue arrow, π interaction.

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Azoalkyl ether imidazo[2,1-b]benzothiazoles 11a–j (Table 7) were described as antibacterial drugs with a wide spectrum of activity against both Gram-positive and Gram-negative pathogens, showing in some cases higher potency than the reference drugs chloromycin (12) and norfloxacin (13). (37) In particular, compound 11d with a propyl linker was up to 8-fold more effective against methicillin-resistant S. aureus (MRSA) and S. typhi eliciting a MIC values of 2 and 1 μg/mL, respectively. To evaluate the capability of derivative 11d to stimulate bacterial resistance, a time-kill kinetic experiment was performed on MRSA. The results highlighted an instant bactericidal effect against MRSA without effects on the onset of antibiotic resistance. The possible mechanism of action was investigated through (i) a docking study aiming to evaluate the interaction of derivative 11d with the binding site of S. aureus DNA gyrase (PDB 2XCS) and (ii) a UV–vis spectroscopic analysis to clarify the binding mode with MRSA DNA. The computational study disclosed the possibility of compound 11d to interact with the complex of gyrase–DNA by π–π stacking between the two carbonyl groups of the imidazo[2,1-b] benzothiazole backbone and base pairs DG-11 and DG-10 of DNA. The nitrogen atom of the azole cycle was able to form a hydrogen bond with Met1121, whereas the nitro group bond to residue Asp1083 (Figure 6). Additionally, UV–vis spectroscopy showed that compound 11d is capable to enter into MRSA–DNA, preventing the replication process of DNA.
Table 7. Chemical Structures and Antibacterial Activity of Compounds 11a–j, Chloromycin (12), and Norfloxacin (13)

Figure 6

Figure 6. Schematic representation of the binding of compound 11d into the active site of S. aureus DNA gyrase. Hydrogen bonds in blue dashed lines.

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Schiff bases constitute a class of compounds endowed with a broad spectrum of biological activity, probably ascribable to the presence of the electrophilic carbon atom and the nucleophilic nitrogen atom of the imine group, which may provide precious binding sites for the interaction with the biological target. Schiff bases also demonstrate to be sufficiently stable in in vitro and in vivo assays. (38) On the basis of this knowledge, a series of Schiff bases of thiazolyl-triazole 14a–g (Table 8) were reported as antibacterial compounds and potential DNA gyrase inhibitors. (39) All of these compounds were evaluated against the Gram-positive S. aureus ATCC 49444 and Listeria monocytogenes ATCC 19115 and the Gram-negative P. aeruginosa ATCC 27853 and S. typhimurium ATCC 14028. L. monocytogenes was the most susceptible strain, with MIC values of 1.9–3.9 μg/mL, which are lower than ciprofloxacin (15). Among the Gram-negative, P. aeruginosa was potently inhibited by derivatives 14a–g (MIC = 1.9 μg/mL). The ratio between MBC and MIC disclosed a bactericidal effect for these molecules. Docking studies on the DNA gyrase from L. monocytogenes suggested a mechanism of action in which this enzyme is involved. In particular, all the Schiff bases seem to prevent the entry of O-(5′-phospho-DNA)-tyrosine intermediate in the binding site.
Table 8. Chemical Structures and Antibacterial Activities of Compounds 14a–g and Ciprofloxacin (15)
    MIC (μg/mL)
compd Ar S. aureus ATCC 49444 L. monocytogenes ATCC 19115 P. aeruginosa ATCC 27853 S. typhimurium ATCC 14028
14a 4-Br-phenyl 31.2 1.9 1.9 62.5
14b 4-F-phenyl 31.2 1.9 1.9 62.5
14c 4-NO2-phenyl 62.5 1.9 1.9 62.5
14d 2-OCH3-phenyl 31.2 1.9 1.9 62.5
14e 3-OCH3-phenyl 31.2 1.9 1.9 31.2
14f 2-thienyl 15.6 1.9 1.9 62.5
14g 4-(CH3)2N-phenyl 31.2 1.9 1.9 62.5
15   1.9 3.9 3.9 0.97
Eakin et al. identified a series of pyrrolamides with potent DNA gyrase inhibitory activity, employing a fragment-based lead generation approach (FBLG) with NMR screening to discover compounds with low molecular weight able to bind the ATP-binding pocket of E. coli GyrB. (40) Starting from almost 1000 compounds with molecular masses ranging from 100 to 370 Da, the pyrrole 16 (Figure 7) showed a DNA gyrase IC50 of 3 μM and was chosen as the lead compound for the design of more potent inhibitors. The structural optimization of pyrrolamide 16 had mainly the purpose of improving the antibacterial activity of this class of compounds. In fact, despite its potent inhibitory activity against the enzyme, the compound 16 was ineffective in vitro against the tested bacterial strains (E. coli ARC523, E. coli ARC524, Haemophilus influenzae KW20, S. aureus ARC516, S. pneumoniae ARC548, Enterococcus faecium ARC521). Structural modifications of pyrrolamide 16, suggested by computational and X-ray crystallography studies, created a powerful GyrB inhibitor, incorporating the thiazole nucleus, 17 (Figure 7), endowed with a significant antibacterial activity against S. pneumoniae using a mouse model of lung infection. The crystallographic structure of derivative 16 inside the ATP-binding domain of S. aureus GyrB revealed a common interaction pattern with the natural substrate, in particular, the pyrrole moiety occupied the same pocket of the ATP adenine, creating a hydrogen bond with Asp81, whereas, the carbonyl group was involved in a hydrogen bond with a conserved water molecule.

Figure 7

Figure 7. Graphic representation of the binding mode of compounds 16 and 17. Hydrogen bonds are represented with dashed blue lines, while hydrophobic interactions are in yellow.

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The introduction in compound 17 of the two chlorine atoms in the pyrrole moiety proved to be particularly advantageous for the affinity toward the enzyme. These atoms indeed increased the hydrophobic interactions with the adenine pocket and because of their electron withdrawing effect and improved the ability of the pyrrole NH group in establishing a hydrogen bond with the Asp81. Moreover, the presence of a carboxyl group on the thiazole ring enhanced the affinity toward the enzyme, forming two additional hydrogen bonds with the Arg144 of the active site. Pyrrolamide 17 showed MBC values against S. aureus, H. influenzae, and S. pneumoniae of 8, 4, and 0.5 μg/mL, respectively, eliciting no cytotoxicity toward mammalian cells.
The ability of 17 to induce spontaneous resistance was evaluated at the concentration of 8 μg/mL in S. aureus ARC516 and a frequency of 2.5 × 10–9 was observed. Importantly, in vivo efficacy of compound 17 assessed in an S. pneumoniae lung infection model in mice (1 × 105 CFU/lung) has been found at the oral dose of 160 mg/kg.
The fluorine atom on the 3-piperidine position characterizes 18 (Figure 8), which was obtained as mixture of four possible distereoisomers, including the (3S,4R)-distereoisomer, which showed enhanced inhibitory activity against DNA gyrase and antibacterial potency. The presence of fluorine atom, which occupied a region close to the hydrophobic pocket of the enzyme, determined an improvement in the activity by 4–8-fold. This might be due to a modification in the piperidine conformation, which allowed stronger interactions of the pyrrole carboxamide and the thiazole carboxylate with the Asp81 and Arg84, respectively. Additionally, the carboxyl group of the thiazole ring is involved in a salt bridge with Arg144 (Figure 9). This new enantiomerically pure thiazole analogue showed improved in vivo potency against S. pneumoniae in a mouse model of pneumonia. (41) The compound was orally administered 18 h postinfection with 105 CFU/lung of S. pneumonia ARC548, and the in vivo activity was evaluated through viable counts in dilutions of lung homogenates. A dose-dependent reduction in viable bacterial counts in the lung was observed, eliciting the highest response at the dose of 80 mg/kg.

Figure 8

Figure 8. Chemical structures of compound 18 and AZD5099(19).

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Figure 9

Figure 9. Representative model of the binding mode of compound 18 in complex with S. aureus GyrB (3TTZ) illustrated by ball and stick design.

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Further SAR studies, carried out with purpose of optimizing the structure of these compounds, resulted in the identification of the antibacterial agent AZD5099 (19) (Figure 8), which entered phase I clinical trials as a novel treatment of Gram-positive and Gram-negative infections. (42) The replacement of the fluorine atom at the 3-position of the piperidine scaffold with a methoxyl group was particularly advantageous in terms of enzyme inhibitory activity and antibacterial properties. Additionally, the carboxylic group in the thiazole nucleus was crucial for the activity because it is involved in a salt bridge interaction with the residue Arg144. AZD5099 (19) proved to be efficacious in different in vivo models, in particular, for cure of nosocomial lung and skin infective diseases caused by relevant Gram-positive such as S. aureus. Studies on the pharmacokinetic and bioavailability highlighted the suitability of AZD5099 (19) for both parenteral and oral administration.

3. Modulators of Bacterial Cell Wall Synthesis and Permeability

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3.1. MurB Inhibitors

The MurB enzyme is an NADPH dependent UDP-N-acetylenolpyruvylglucosamine reductase that plays a key role in the second step of bacterial peptidoglycan biosynthesis.
In particular, the Mur pathway enzymes MurA and MurB catalyze the synthesis of UDP-N-acetylmuramic acid (UDP-MurNAc) from UDP-N-acetylglucosamine (UDP-GlcNAc). Subsequently, MurC, MurD, MurE, and MurF add amino acids to UDP-MurNAc and generate the UDP-MurNAc-pentapeptide, which is incorporated into the nascent bacterial peptidoglycan. (43) MurB emerged as an interesting target for novel antibacterial drugs for many reasons: (i) its inhibition leads to a bactericidal effect because it is fundamental for the bacterial growth, (ii) there is no analogue in the eukaryotic cell therefore the selectivity should be easily obtainable, and (iii) being present in both Gram-positive and Gram-negative pathogens its inhibition should result in a broad spectrum antibacterial activity (Figure 10). (44)

Figure 10

Figure 10. Representative examples of small molecules with MurB inhibitory activity.

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Among the thiazole compounds, 4-thiazolidinones, which are the tetrahydro derivative of thiazole bearing a carbonyl group, are widely described in recent years as they present different biological activities. (45−50)
The ability of the 4-thiazolidinone scaffold in inhibiting this enzyme was first described in 2000 by Andres and co-workers, who identified three derivatives 20–22 endowed with potent E. coli MurB inhibitory activity at low micromolar level (Figure 10). (51) Among them, the 4-thiazolidinonederivative 21 results the most potent compoundwith an IC50 value of 7.7 μM, which is 2-fold lower than those obtained by derivatives 20 and 22 (IC50 values of 14 and 15 μM, respectively). It was hypothesized, as supported by in silico studies reported by the authors, that 4-thiazolidinone scaffold may act as MurB inhibitor by mimicking the diphosphate group.

3.2. Penicillin Binding Protein Inhibitors

A series of thiazolidinone derivatives 23a–e (Table 9) was synthesized and examined for inhibitory activity toward transpeptidases and β-lactamase. (52)
Table 9. Chemical Structures and Antibacterial Activity of Compounds 23a–e
    MIC values (μg/mL)
compd R S. aureus ATCC 25923 B. subtilis ATCC 6633 E. coli ATCC 25922 P. aeruginosa ATCC 27853
23a Cl 31.25 31.25 125 125
23b CN 62.50 62.50 250 250
23c OCH3 125 125 250 250
23d N(CH3)2 250 250 500 500
23e NO2 15.60 31.25 62.50 125
When assayed against the Gram-positive bacteria S. aureus ATCC 25923 and Bacillus subtilis ATCC 6633, the Gram-negative bacteria E. coli ATCC 25922, and P. aeruginosa ATCC 27853 compounds 23a–e showed MIC values within the range of 15.60–500 μg/mL, exhibiting a strong selectivity toward Gram-positive pathogens. The most active derivative 23e elicited MIC values of 15.60, 31.25, and 62.50 μg/mL against S. aureus, B. subtilis, and E. coli, respectively. Studies on the mechanism of action were carried out by employing the method of Heipieper for evaluating the leakage of UV260 and UV280 (mostly nucleic acid material and protein) absorbing material. In these studies, 23e was able to alter the membrane permeability causing cell death. In addition, docking studies into the active site of penicillin binding protein (PBP) (PDB 1FXV) and β-lactamase (PDB 4FH2) enzymes highlighted a higher affinity for the PTB transpeptidase, supporting the hypothesis of a mechanism of inhibition of the synthesis of peptidoglycan by inhibiting the enzyme PTB transpeptidase. The compound showed a binding pattern similar to that of ampicillin, forming a hydrogen bond with the key residue of the binding site Ser 1B. The determination of the leakage of UV260- and UV280-absorbing material, which mainly consists of nucleic acid material and protein, confirmed that the compound acts by altering membrane permeability.
The authors utilized for their docking studies the conformation reported in Table 9 instead of the preferred topology involving the C═O oxygen atom proximal to S stabilized by an O to S interaction. (13,14) Therefore, the authors have jeopardized the reliability of the obtained results.
Further biochemical studies on the enzyme should be carried out to confirm this hypothetical mechanism of action and for validating the docking results.
The thiazole scaffold is also present in a novel injectable siderophore cephalosporin bearing a catechol moiety, known as cefiderocol (24) (Figure 11), which demonstrated powerful antibacterial activity against Gram-negative pathogens. This activity is caused by the inhibition of penicillin binding proteins and thus interfering with the bacterial cell wall synthesis. (53,54) Cefiderocol (24), although structurally very similar to the third- and fourth-generation cephalosporins ceftazidime (25) and cefepime (26) (Figure 11), elicited higher stability toward different β-lactamases such as AmpC and extended-spectrum β-lactamases.

Figure 11

Figure 11. Chemical structures of cefiderocol (24), ceftazidime (25), and cefepime (26).

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The key role of the aminothiazole ring, common to many broad-spectrum cephalosporins, in enhancing the activity against Gram-negative bacteria is well described. Thus, high resolution crystal structures of the P. aeruginosa PBP3 with many compounds including marketed β-lactams, as well as in silico studies, highlighted that ceftazidime (25) affinity for B3-PBPs was due to the interaction of its aminothiazole ring with the binding pocket. (55) The amino acid residues of the aminothiazole binding pocket are conserved in many B3-PBPs. Therefore, the presence of aminothiazole, determining an increase in the affinity toward these proteins, usually is responsible of the enhancement of activity against Gram-negative bacteria. (56) In fact, none of the many cephalosporin derivatives synthesized using different heterocyclic systems instead of aminothiazole ring showed comparable potency. (57) Additionally, the carboxypropyl-oxyimino group is responsible for the increased stability of the compound toward β-lactamases hydrolysis. Of note, the presence of a catechol group on the side chain improved significantly the periplasmic concentrations of cefiderocol (24), with respect to the other cephalosporins, because of its ability to chelate iron, which makes possible the use of iron transportation systems present in the outer membrane (OM) of Gram-negative pathogens (“Trojan horse strategy”).
Cefiderocol (24) proved to be efficacious against serious Gram-negative infections, showing a strong activity against infections caused by carbapenem-resistant and MDR Gram-negative bacteria, including MDR Enterobacteriales, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. (58) This compound is being investigated in phase III clinical studies. Previous clinical studies highlighted the efficacy and safety of intravenous cefiderocol (24) in patients with complicated urinary tract infections (cUTIs) and in the treatment of many Gram-negative infections, such as healthcare-associated pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia. (59)

3.3. Inhibitors of Heptose Synthesis

Lipopolysaccharide (LPS) is a highly acylated saccharolipid, which constitutes the main component of the outer leaflet of the OM of Gram-negative pathogens. LPS has a crucial role in maintaining the barrier function by avoiding the passive diffusion of hydrophobic solutes such as antibiotics and detergents into the cell. (60)
LPS is formed by lipid A, a core oligosaccharide and a repeating polysaccharide O-antigen. The core oligosaccharide is constituted by an inner core of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) and heptose residues and an outer core of hexoses derivatives.
Inhibition of heptose synthesis leads to vulnerable bacteria with incomplete LPS, which are more sensitive to host defenses and to many antibiotics because of their increased membrane or cell wall permeability. The identification of small molecules interfering with this process is currently recognized as a valuable goal for the development of novel antivirulence agents against Gram-negative pathogens because heptose is not fundamental for Gram-negative survival, but the inhibition of its synthesis causes an attenuation of virulence.
The bacterial synthesis of heptose in E. coli involves many enzymes including the transketolase TktA, the ketose–aldose isomerase GmhA, the kinase HldE, the phosphatase GmhB, and the epimerase HldD. (61) Desroy and collaborators focused their attention on the first step of heptose synthesis, looking for molecules that can inhibit the kinase activity of E. coli HldE. (62)
HldE in E. coli is a bifunctional cytoplasmic ATP-dependent kinase, which uses its two functional domains (carbohydrate kinase and adenylyltransferase) to catalyze the transformation of d-glycero-d-manno-heptose-7-phosphate in d-glycero-β-d-manno-heptose-1,7-bisphosphate and of d-glycero-β-d-manno-heptose-1-phosphate in ADP-D-glycero-β-d-manno-heptose (Scheme 1). (63)

Scheme 1

Scheme 1. Synthesis of ADP-l-glycero-β-d-manno-heptose from Sedoheptulose-7-phosphate and Its Incorporation into LPS
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HldE can be considered a promising target for obtaining antimicrobial agents against Gram-negative pathogens. Because this enzyme is well conserved among bacteria and there are not homologues in humans, the synthesis of selective inhibitors with low toxicity should be feasible. However, heptose synthesis inhibitors are ineffective toward pathogens which have a LPS without heptose such as Acinetobacter, Chlamydia, and Moraxella. (64)
Through a high-throughput screen of 40 000 compounds performed on HldE-kinase activity of E. coli, two new inhibitors 27a,b (Figure 12) were identified. Compounds 27a,b showed IC50 values of 51 and 69 μM, respectively, behaving as competitive reversible inhibitors toward ATP in the reaction catalyzed by HldE kinase. SAR studies of these compounds led to the identification of more potent derivatives bearing the benzothiazole scaffold. The effect on the HldE kinase activity of various substituents on the phenyl ring was evaluated, and it was observed that (i) the presence of an amino group in ortho or para position was particularly advantageous for the activity, while, in contrast, it caused a loss of potency in meta position, (ii) a nitro group in ortho or in para position was detrimental for the activity, whereas it proved to be favorable in meta, (iii) trifluoromethyl and methoxy groups afforded an improvement in the activity in meta position but caused significant reduction in activity in ortho and para and, finally, (iv) a bromine atom was advantageous for the activity in any position. The replacement of the phenyl ring with heteroaromatic rings or with an ethyl group led to inactive compounds, highlighting the key role of the phenyl moiety for the activity on HldE kinase. In contrast, the oxazole core could be substituted with other heterocycles including thiazole, furan, or pyrazole without any effect on the activity. These results underlined also the importance of the carboxylic acid on the amide side chain because its replacement with other groups, such as amide, alcohol, acylsulfonamide, or tetrazole, led to inactive derivatives. On the basis of these findings and of the observation that the meta substitution of the phenyl ring was also relevant for the activity, a derivative 28 (Figure 12), bearing a pyrazole ring in that position, was synthesized and evaluated for its activity against HldE kinase. Among the derivatives of this series, compound 28 elicited the highest activity with an IC50 against the enzyme of 0.11 μM.

Figure 12

Figure 12. Chemical structures of compounds 27a,b and 28.

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The inhibitory activities against HldE-kinase and ribokinase (RK) of E. coli and HldA of Neisseria meningitidis (the equivalent of HldE-kinase in E. coli), which share a very similar ATP binding site, were also compared and the results showed a significant selectivity toward HldE/HldA enzymes of Gram-negative bacteria. These compounds are able to interfere with heptose synthesis, altering the barrier function of the LPS but showing no effects on E. coli viability, displayed the typical profile of an antivirulence agent. Such compounds, acting on virulence factors without interfering with the bacterial life cycle, impose low selective pressure for the development of bacterial antibiotic resistance mechanisms.
Other benzothiazole derivatives acting as membrane perturbing agents able to depolarize the cytoplasmatic membrane of S. aureus and E. coli are compounds 29a,b and 30a,b (Figure 13). (65) When assayed for their antibacterial activity against S. aureus (ATCC 25323), E. coli (ATCC 35218), P. aeruginosa (ATCC 27893), K. pneumonia (ATCC 31488), E. faecalis (clinical isolate), and S. typhi (MTCC 3216), the benzothiazole 29a, bearing a chlorine atom and a methoxy group on the phenyl ring, demonstrated the highest potency with MIC values in the range of 3.91–31.2 μg/mL. The effects of this series in perturbing the permeability of S. aureus and E. coli membrane was evaluated by using the cationic membrane potential-sensitive cyanine dye, which allows a determination of the alteration of membrane potential and the formation of pores, caused by the compounds, by an increase in fluorescence intensity. Compounds 29a,b were able to damage the membrane structure in S. aureus and E. coli causing the dispersion of the bacterial cell contents. It was observed that, after interaction with the membrane, compounds 29a,b and 30a,b entered into the cytoplasm and bound to bacterial DNA enhancing the antibacterial effect due to the membrane permeabilization.

Figure 13

Figure 13. Chemical structures of compounds 29a,b and 30a,b.

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4. Tryptophanyl-tRNA Synthetase Inhibitors

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The aminoacyl-tRNA synthetases are enzymes with important roles in RNA translation because they catalyze the aminoacylation reaction by covalently linking an amino acid to its corresponding tRNA. (66) These enzymes are essential in bacterial growth and survival because they are involved in many metabolic and signaling pathways essential for cell viability. (67)
Compounds that are able to selectively inhibit the bacterial aminoacyl-tRNA synthetases without interfering with their mammalian analogues can be useful candidates for the development of new classes of antimicrobial agents.
Recently, Stana and co-workers reported a series of thiazolin-4-one derivatives 31 (Figure 14) endowed with moderate to good antibacterial activity against the Gram-negative bacterial strain E. coli ATCC 25922 and the Gram-positive bacterial strain S. aureus ATCC 49444. (68) All compounds were more effective against Gram-positive pathogens, and compounds 31a and 31b showed MIC and MBC values against S. aureus ATCC 49444 of 0.97 and 1.95 μg/mL, respectively. Because of the structural similarity between compounds 31a and 31b with the known tryptophanyl-tRNA synthetase (TrpRS) inhibitor indolmycin (32), the authors hypothesized a mode of action involving TrpRS inhibition.

Figure 14

Figure 14. Chemical structures of compounds 31a,b and of the known TrpRS inhibitor indolmycin (32).

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The affinity of the new compounds toward the TrpRS from S. aureus (1I6K_P67592) and E. coli (5 V0I) was evaluated in silico through molecular docking studies. Results revealed a good affinity of the thiazolin-4-ones due to the formation of polar contacts between exocyclic secondary amine group and the carbonyl group from the thiazolin-4-one ring with amino acid residues of the binding site of the enzyme. Most of the synthesized compounds showed, in silico, better affinity toward TrpRS than the reference compound indolmycin (32). The best binding affinity was observed for the compounds incorporating voluminous moieties, such as the α-naphthylamino group, at position 2 of the thiazolin-4-one ring.
Molecular docking studies suggested the key role of the thiazolin-4-one scaffold in polar interactions with the TrpRS binding site. Most compounds showed a common binding pattern involving the carbonyl group of the thiazolin-4-one in the case of S. aureus TrpRS. Additionally, the nitrogen atom of the thiazolinone ring hypothesized to be responsible of a polar interaction with the Gly9 residue of the binding site of the most active derivative 31b against E. coli.

5. Sortase A (SrtA) Inhibitors

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SrtA is a cysteine transpeptidase which anchors the surface proteins, MSRAMMs, to the peptidoglycan of the bacterial cell wall in Gram-positive pathogens. After the recognition of the LPXTG motif in MSRAMMs, SrtA catalyzes the following reactions: (i) thioesterification in which the enzyme cleaves the LPXTG between Thr and Gly, leading to the synthesis of thioester acyl-enzyme intermediate and (ii) the transpeptidation, which allows the formation of a bond between the C-terminal Thr residue of the protein to pentaglycine cross-bridges. The pivotal role of this enzyme in bacterial adhesion and bacterial pathogenesis is well documented and represents therefore an excellent potential target for antivirulence drug development because it is involved in the adhesion of bacteria to host tissues and in biofilm formation, but it is not essential for bacterial viability. (69) Additionally, SrtA is a membrane enzyme, therefore much more easily accessible than intracellular targets, and there are no analogues of this enzyme in humans so SrtA inhibitors should have low toxicity and high selectivity.
A new series of 2-phenylthiazole derivatives 33a–h (Table 10) were synthesized as SrtA inhibitors. (70) The antimicrobial activity of the new compounds was tested against five Gram-positive and two Gram-negative bacterial strains. All of the compounds showed good activity against S. aureus, in which the lowest MIC value (16 μg/mL) was observed for derivative 33f. The highest potency was reached by the chlorophenyl derivative 33h toward Staphylococcus saprophyticus ATCC 15305 (MIC = 2 μg/mL).
Table 10. Chemical Structures, Antibacterial Activities, and Antibiofilm Activities of Compounds 33a–h
      MIC (mg/mL) BIC (mg/mL)
compd Ar R E. faecalis S. saprophyticus E. faecalis
33a Ph CH3 0.25 >1.0 0.004
33b Ph H 0.125 0.032 0.002
33c 4-NO2-Ph H 0.062 0.032 0.002
33d 4-OCH3-Ph H 0.062 0.125 0.004
33e 4-CN-Ph H 0.062 0.016 0.002
33f 1-naphthalene H 0.016   0.004
33g 3-CONH2,4-OH-Ph H 0.25   0.008
33h 4-Cl-Ph H 0.032 0.002 0.016
Because the inhibition of SrtA is correlated to the inhibition of biofilm formation in Gram-positive pathogens, the derivatives were also evaluated for their antibiofilm properties against all the tested strains.
These compounds proved to be more potent against E. faecalis, showing BIC50, which is defined as the lowest concentration of compound that showed 50% inhibition on the biofilm formation, in the range 2–16 μg/mL. Aiming at corroborating the mechanism of action involving SrtA, molecular docking studies evaluated the active sites of SrtA from both bacterial species. Results highlighted higher affinity toward E. faecalis SrtA and a common binding pattern, which involved the thiazole nucleus in polar contacts through the nitrogen atoms with the hydroxyl group of Thr122. The presence of polar substituents on the phenyl ring at position 4 of the thiazole nucleus enhanced the affinity toward the transpeptidase through the formation of additional hydrogen bonds with the residues Arg224 and Asn221. Despite the fact that the in silico results were in line with the results of biofilm analyses, highlighting more favorable binding in the case of E. faecalis respect to S. aureus, further in vitro tests are warranted in order to confirm this mechanism of action.

6. Antibiofilm Compounds

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Biofilm is studied as one of the critical bacterial virulence factor responsible for serious chronic infections which proved to be resistant to the majority of antibiotic therapies. (71)
Despite, many investigations focused on the development of novel antivirulence compounds with an antibiofilm mechanism of action, (72,73) no antibiofilm agents have entered in the clinical practice. This is mainly caused by the lack of in vivo experiments for validating the efficacy of the new agents in preventing biofilm-associated infection.
At present, more than 80% of chronic infectious diseases are biofilm-mediated, therefore new strategies able to combat the formation of biofilm or to eliminate preformed biofilm are urgently needed. The identification of new agents that can inhibit bacterial biofilm but are not affecting microbial growth could lead the development of new antivirulence strategies with reduced selective pressure for the onset of drug resistance.

6.1. 4-Thiazolidinone Derivatives

Coagulase-negative S. epidermidis is currently considered the most common source of infection related to implanted medical devices. The ability of S. epidermidis to create biofilms on the facets of medical devices, significantly more resistant to standard antibiotics with respect to the planktonic form, often determine serious chronic infection. Starting from the knowledge on the interesting antibiofilm and antibacterial activity (BIC50 = 15.52 μg/mL, MIC = 3.88 μg/mL) of 3-(5-((6-(ethoxycarbonyl)-5-(benzo[1,3]dioxol-5-yl)-3-oxo-7-phenyl-thiazolo[3,2-a]pyrimidin-2(5H)-ylidene)methyl)furan-2-yl)benzoic acid 34 (Figure 15) against S. epidermidis, (74) Pan and collaborators designed novel thiazolidiones 35 (Table 11) in order to synthesize more effective S. epidermidis biofilm inhibitors. (75,76) The strongest compound, 35e, resulted in 4-fold more activity in dispersing S. epidermidis preformed biofilm (BIC50 = 3.08 μg/mL) and in inhibiting bacterial growth of the planktonic form (MIC = 1.54 μg/mL) than the parent compound 34.

Figure 15

Figure 15. Chemical structures of compound 34.

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Table 11. Chemical Structures, Antibacterial Activities (MIC50, μg/mL), and Antibiofilm Activities (BIC50, μg/mL) of Derivatives 35a–e
compd R1 R2 MIC50S. epidermidis BIC50S. epidermidis
35a 4-OCH3-Ph-CH2– 3-COOH 27.73 55.46
35b 4-OCH3-Ph– 3-COOH 3.29 3.29
35c 4-CH3-Ph-CH2– 3-COOH 3.27 6.54
35d 2-CH3-Ph-CH2– 3-COOH 6.54 13.08
35e 2-CH3-Ph– 4-COOH 1.54 3.08
The marine alkaloid oroidin showed a BIC50 against P. aeruginosa biofilms of 190 μM. To create more potent antibiofilm compounds, a series of 4-thiazolidinone derivatives 36 (Table 12) of the marine bromopyrrole was developed and evaluated for both antibacterial and antibiofilm activity against S. epidermidis ATCC 12228, S. aureus ATCC29213, and E. faecalis ATCC 29212. All of these compounds displayed encouraging effects against the tested strains. (77)
Table 12. Chemical Structures and Antibacterial Activities (BIC50, μg/mL) of Derivatives 36a–i and 37a,b
compd R1 BIC50S. aureus
36a Ph 3.125
36b 4-OCH3-Ph 0.78
36c 4-NO2-Ph– 0.78
36d 2-OH,4-OCH3-Ph– 1.56
36e 3-OH,4-OCH3-Ph– 3.125
36f 2,5-OH-Ph– 1.56
36g 4-F-Ph– 1.56
36h 4-Cl-Ph– 1.56
36i cinnamyl 6.125
37a 4-OCH3-Ph 6.25
37b 4-NO2-Ph– 6.25
Importantly, compounds 36b and 36c were 3-fold more potent than the reference drug vancomycin, demonstrating antibiofilm effects against S. aureus ATCC29213 at a concentration of 0.78 μg/mL.
Biological data revealed the importance of the 1,3-thiazolidin-4-one group for the antibiofilm activity, in fact, its replacement with a six-membered ring such as the 1,3-thiazinan-4-ones led to a significant decrease in the activity, as it was demonstrated by the BIC values of compounds 37a,b; the corresponding six-membered analogues of the most active compounds 36b,c.
The condensation of the 4-thiazolidinone ring with a pyrimidine nucleus led to compounds 38a–d (Table 13) that showed antibacterial activity against staphylococcal strains, with MIC values in the range of 0.95–3.82 μg/mL. In addition, all of these compounds exhibited promising antibiofilm activity at 30 μg/mL. The assay of inhibitory activity on YycG histidine kinase suggested that the antibacterial activity of the most promising compound 38a is based on inhibiting this enzyme (IC50 of 7.73 μg/mL), which is an indispensable enzyme in the signal transduction pathway for the cell-wall metabolism. (78)
Table 13. Chemical Structures and Antibacterial Activities (MIC, μg/mL) of Derivatives 38a–d
compd R1 R2 S. epidermidis ATCC35984 S.epidermidis ATCC12282 S.aureus ATCC25923
38a 4-Cl 3-COOH 0.95 1.91 3.82
38b 4-F 3-COOH 3.72 1.86 3.72
38c 4-Cl 4-COOH 3.82 1.91 3.82
38d 4-F 4-COOH 3.72 3.72 3.72

6.2. Thiazoles

Because the antibacterial activity of thiazoles and different types of Schiff bases is widely documented, (79,80) a new series of 4-(o-methoxyphenyl)-2-aminothiazoles 39 (Figure 16) was prepared by a microwave-assisted synthesis and evaluated for its antibacterial and antibiofilm effect against P. aeruginosa, Bacillus subtilis, and E. coli. (81) The best antibacterial activity was observed for compounds 39a and 39b against the planktonic form of B. subtilis, with MIC values ranging from 25 to 50 μg/mL.

Figure 16

Figure 16. Chemical structures of compounds 39a,b, sulfathiazole (40), ceftriaxone (41), aztreonam (42), and compounds 43a,b.

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These derivatives were also studied with scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM) analysis in order to evaluate their biofilm inhibition in P. aeruginosa, and a significant reduction in the formation of biofilm was found at subinhibitory concentrations. Obtained results suggested a quorum sensing (QS) mediated inhibition of biofilm formation, it being regulated by an intercell communication system aided by released chemical signals.
The QS system is recognized as an appealing target for the development of efficacious antivirulence agents. Because QS is not directly implicated in vital and growth processes of bacteria, its modulation imposes only a minor pressure for the development of mechanisms underlying antibiotic resistance. A therapeutic strategy that fights QS signaling, rather than the bacteria life cycle, may find application in different fields including medicine, agriculture, and food technology.
2-Amino-1,3-thiazole scaffold is known as a qualified pharmacophore for the development of antibacterial agents and other biologically active molecules. (82) Numerous molecules bearing the 2-aminothiazole structural motif, including sulfathiazole (40), ceftriaxone (41), and aztreonam (42), have reached the clinical or preclinical phase. On the basis of the interesting antibacterial property described for this nucleus, Stefanska and co-workers synthesized a library of novel thiourea derivatives of type 40 (Figure 16), which were examined in vitro against several microorganisms, including relevant Gram-positive and Gram-negative pathogens. (83)
Compounds 43a and 43b showed the most promising activity against the staphylococcal planktonic forms eliciting MIC values toward MRSA strains and S. epidermidis in the range of 4–16 μg/mL.
The antimicrobial activity is affected by the type and the position of the substituent on phenyl ring. In particular, the 3-chloro-4-fluorophenyl substituted 43b showed the strongest activity against both standard and hospital Gram-positive pathogen strains.
These thiourea conjugates 43 were further tested, at concentrations 1–16 μg/mL, to evaluate their ability to inhibit the formation of the formation of biofilm in eight methicillin-resistant (MRSE) and two standard (ATCC 12228, ATCC 35984) strains of S. epidermidis. In addition to the antimicrobial activity against the free-swimming forms, compounds 43a and 43b were the most effective antibiofilm agents, with IC50s ranging from 0.35 to 7.32 μg/mL.
Marine natural products (MNP) or marine-derived molecules, such as marine sponge-derived compounds, have been under the spotlight because of their exclusive biodiversity and different structural features as compared to terrestrial products. (84) Eight of these compounds are used in a number of therapeutic areas, while other compounds are under development in different phases of the clinical pipeline. Only a minority are original MNPs, while most of these compounds are derivatives synthesized through molecular lead optimization. (85)
Bis-indolyl alkaloids, which have two indole units bound to a spacer through their position 3, represent a class of deep-sea sponge metabolites with powerful biological effects, mainly antitumor (86−88) and antimicrobial properties. (89−94)
Recent studies showed the antibiofilm activity of the new series of bis-indolyl alkaloid nortopsentin analogues 44 in which the imidazole core of the natural product is substituted by the thiazole ring. (95) Compounds 44a–l (Table 14) did not affect the growth of the planktonic form of the Gram-positive S. aureus ATCC 25923, S. aureus ATCC 6538, and the Gram-negative P. aeuruginosa ATCC 15442 bacteria, showing MICs above 100 μg/mL.
Table 14. Chemical Structures and Inhibition of Biofilm Formation (IC50, μg/mL) of Thiazole Derivatives 44a–l
compd R R1 R2 S. aureus ATCC 25923 (μg/mL) S. aureus ATCC 6538 (μg/mL) P. aeuriginosa ATCC 15442 (μg/mL)
44a H CH2CH2NHBoc H 3.9 ± 0.2 5.2 ± 0.3 ns
44b H CH2CH2NH2 H 4.7 ± 0.3 9.7 ± 0.9 22.7 ± 2.1
44c Br CH2CH2NH2 H 4.4 ± 0.1 3.3 ± 0.08 7.8 ± 0.09
44d F CH2CH2NH2 H 1.5 ± 0.1 6.3 ± 0.4 4.5 ± 0.4
44e F CH2CH2NH2 CH3 0.5 ± 0.02 5.2 ± 0.08 3.9 ± 0.07
44f OCH3 CH2CH2OCH3 CH3 1.2 ± 0.03 11.5 ± 0.7 ns
44g Br CH2CH2OCH3 H 0.79 ± 0.009 9.4 ± 0.3 4.4 ± 0.08
44h Br CH2CH2OCH3 CH3 0.95 ± 0.01 11.2 ± 1.1 19.1 ± 0.1
44i Br CH2CH2OCH3 CH2CH2OCH3 2.9 ± 0.02 18.8 ± 1.5 ns
44j Br CH3 CH2CH2OCH3 2.5 ± 0.02 ns ns
44k F CH2CH2OCH3 CH3 0.2 ± 0.006 21.0 ± 1.7 ns
44l H Boc CH2CH2OCH3 1.8 ± 0.1 6.9 ± 0.1 ns
Almost all derivatives were strong inhibitors of the formation of staphylococcal biofilm (Table 14). Thiazole derivatives 44e, 44g, 44h, and 44k were the most active against S. aureus ATCC 25923, showing IC50s of 0.5, 0.79, 0.95, and 0.2 μg/mL, respectively.
The lack of activity of the compounds 44 against the planktonic form was desirable in order to obtain antivirulence agents, which cause only a low selective pressure for the development of antibiotic-resistant strains. All of the new compounds were also evaluated at the concentration of 100 μg/mL to examine their capability to disperse preformed biofilm. However, none of these derivatives was able to disrupt biofilm architecture. Compounds 44 interfered with the first step of the formation of biofilm without effecting microbial growth nor preformed-biofilm, showing a significant selectivity against the Gram-positive pathogens respect to the Gram-negative. A mechanism of action involving the inhibition of the transpeptidase SrtA was hypothesized. (96,97) Compounds 44a and 44l, which showed the best biofilm formation inhibitory effects as well as the highest selectivity against Gram-positive pathogens, were chosen to validate this hypothesis. Unfortunately, only compound 44a was able to moderately inhibit SrtA at the concentration of 100 μM, with a percentage of inhibition around 48%. Therefore, the antiadhesion activity observed for these derivatives was not correlated to the inhibition of the transpeptidase.

6.3. Benzothiazoles

The synthesis of hybrid molecules bearing two or more biologically active scaffolds in the same structure, is currently considered a promising approach in order to obtain new therapeutic strategies to treat antibiotic-resistance. The main advantage of this approach consists in the simultaneous presence of two pharmacophores, which can lead to a synergism of the biological activities, thus obtaining molecules able to act toward more than one target. (98,99)
Gondru and co-workers adopted the hybridization approach for the design of the new molecules 45a–g (Table 15), which bear simultaneously in one molecular framework the four pharmacophores pyrazole, thiazole, coumarin, and benzothiazole. (100)
Table 15. Chemical Structures and Antibacterial Activity of Compounds 45a–g
Compounds 45a–g were evaluated for their antibacterial activity in vitro against Gram-positive (S. aureus MTCC 96, B. subtilis MTCC 121, S. aureus MLS16 MTCC 2940, Micrococcus luteus MTCC 2470) and Gram-negative pathogens (Klebsiella planticola MTCC 530, E. coli MTCC 739, P. aeruginosa MTCC 2453), and almost all of these derivatives showed antimicrobial activity at concentrations in the low micromolar range. The strongest derivative 45a displayed MIC values against all the tested strains in a range of 1.9–7.8 μg/mL. Biofilm inhibition assay revealed promising antibiofilm activity of compound 45e against S. aureus MTCC 96, with a BIC50 of 7.8 μg/mL. Additionally, derivative 45f elicited biofilm inhibitory activity against S. aureus MTCC 96, S. aureus MLS16 MTCC 2940, K. planticola MTCC 530, and E. coli MTCC 739, with BIC50 values in the range of 8.3–32.6 μg/mL.
The toxicity profile of these compounds was investigated against RAW 264.7 macrophages at concentrations of 2.5× and 10× MIC and, unfortunately, derivatives 45a–g were toxic at the lowest tested concentration. It was hypothesized that the high toxicity of this series was related to the presence of the benzothiazole ring, which undergoes ring-opening generating hydroxylamines with mutagenic and carcinogenic properties. However, this hypothesis was not evaluated in further experimental studies.
GroEL is a homo-oligomeric complex composed of 14 58 kDa subunits arranged in two seven-membered rings stacked back to back, which plays an important role in refolding polypeptides through a process very different from the other molecular chaperones. The folding reaction mediated by GroEL is an ATP-dependent reaction, and it requires a co-chaperone, named GroES. (101) Because the GroEL/ES system has a key function for bacterial viability, the identification of small molecule able to block such function should be an innovative antibacterial strategy.
With the aim to identify new antimicrobial agents able to perturb protein folding pathways, Kunkle and co-workers performed a high-throughput screen for novel inhibitors of the GroEL/ES folding cycle. (102) They identified 235 inhibitors of the E. coli GroEL/ES chaperonin system and selected a subset of 22 compounds to be further evaluated for their antibacterial activity against the so-called “ESKAPE” pathogens (Klebsiella pneumonia, Acinetobacter baumannii, P. aeruginosa, and Enterobacter cloacae). (103) The results allowed the identification of the benzothiazole 46a (Table 16) as a hit compound for the synthesis of a novel class of antibacterial agents because it showed comparable bactericidal effects to vancomycin against S. aureus without toxic effects on human liver (THLE-3) or kidney (HEK 293) cell lines. Optimization of 46a has allowed the observation that (i) the presence of a benzothiazole group and the R2-hydroxyl are essential for robust inhibition, and (ii) the halogenation at the R1 position with a chlorine atom and at R3/R4 positions with a bromine atom further increases the GroEL/ES inhibitory activity. The strongest compounds of the series (46a–d) are reported in Table 16. Their effectiveness in the inhibition of GroEL/ES-mediated folding cycle was evaluated by using E. coli GroEL/ES as the surrogate chaperonin system for refolding of the enzymes malate dehydrogenase (MDH) and rhodanese (Rho). The results highlighted a strong correlation between the activities toward the two refolding assays, showing in the case of derivatives 46a–c IC50 values in the 0.70–4.7 μg/mL range against both systems. Even if studies on the selectivity of these compounds revealed a high affinity also toward the human heat shock protein HSP60/10, the selectivity indices of antibacterial activity and cytotoxicity against human kidney or liver cells were >50-fold.
Table 16. Chemical Structures of Compounds 46a–d and Their EC50 Values for Inhibitors Tested in Assays for the Formation of Biofilm and Penetration/Bactericidal Activity
        S. aureus proliferation and biofilm assay EC50 [μg/mL]
compd R1 R2 R3 planktonic growth preventing biofilm formation killing bacteria in biofilms
vancomycin       0.97 0.78 >145
46a Cl Br Br 0.20 0.41 1.37
46b Cl Br H 0.22 0.49 2.75
46c H Br Br 0.23 0.29 1.23
46d H H H 0.07 0.34 0.76
Compounds 46a–d showed a potent antibacterial activity against the planktonic form of S. aureus with EC50s in the range from 0.07 to 0.23 μg/mL. Most importantly, the GroEL inhibitor 46a was particularly effective toward MRSA strain without generating antibiotic resistance when tested following the procedure described by Kim and collaborators to evaluate the ability of compounds to induce drug resistance. (104)
Compounds 46a–d also prevented S. aureus biofilm formation eliciting BIC50 values of only 0.29–0.49 μg/mL. Being the derivatives equipotent against the planktonic form of the same strain, it is possible that the antibiofilm effect of these compounds is strongly associated with the antibacterial property. Therefore, the authors investigated the ability of this series to kill the bacterial cells inside the biofilm, evaluating their activity on preformed biofilm. In these experiments, compounds 46a–d showed EC50 values from 5 to 15-fold higher than the MICs, but they had however higher activity than the reference drug vancomycin.
In an attempt to obtain new compounds able to overcome the antibiotic-resistance of S. aureus, a dibenzyl (benzo[d]thiazol-2-yl(hydroxy)methyl) phosphonate 47 (Figure 17) was prepared and tested for its antibacterial and antibiofilm properties against strains of S. aureus resistant to penicillin, ampicillin, and methicillin. (105) Phosphonates are valuable organophosphorus scaffolds characterized by the presence of a stable C–P bond, which is usually resistant to biochemical and photochemical destruction. The electron withdrawing effects of the thiazole ring may contribute to enhance its stability. The biofilm inhibitory activity of compound 47 was evaluated both as inhibition of biofilm formation and as disruption of preformed biofilm. This phosphonate derivative exhibited an interesting activity against the planktonic form and against the biofilms of S. aureus ATCC12600 as well as 12 different drug-resistant strains. It indeed determined the maximum of the activity at the concentration of 160 μg/mL with the total disappearance of bacterial aggregates. Studies on the mechanism of action revealed the lysis of Protein-A (FnBPA), which is an important surface protein belonging to the MSCRAMMs that binds fibronectin and fibrinogen and thus is a key determinant in biofilm formation and colonization. (106)

Figure 17

Figure 17. Chemical structures of compounds 47, 48, and 49.

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P. aeruginosa is among the most important biofilm-forming strains of Gram-negative pathogens and commonly causes serious chronic infections, especially in the respiratory system of patients suffering from cystic fibrosis. In P. aeruginosa biofilms, the matrix is essentially constituted by three different extracellular polymeric substance (EPS) molecules: alginate, Pel, and Psl, which are different for their chemical structure as well as for their biosynthetic mechanisms. (107)
The roles of Pel and Psl in antibiotic resistance, biofilm formation, and immune evasion are well-known. Their overproduction is correlated to a considerable increase in bacterial virulence. (108) Pel also has important functions in cross-linking eDNA and consequentially in forming the biofilm structure. Deletion of pelB results in a severe biofilm decrease, whereas Psl forms fiber-like structures which are fundamental in interactions at cell surface, matrix development, and architecture of the biofilm. The Pel and Psl involvement in antimicrobial resistance has been widely investigated: Pel proved to be crucial for the resistance to aminoglycosides, (109) while Psl is responsible for the tolerance to polymyxins, aminoglycosides, and fluoroquinolone antibiotics by sequestering them and also by reducing the recognition by the immune system. (110)
With the aim of obtaining novel inhibitors of P. aeruginosa biofilm formation targeting Pel and Psl and consequently the EPS secretion, Bernardes and collaborators carried out a high-throughput screen (HTS) for repressors of the gene expression of EPS, pelB::lux. (111)
Among the pel repressors identified, the benzothiazole derivatives 48 and 49 (Figure 17) showed significant antibiofilm activity against PAO1. These compounds were further evaluated for their antivirulence effect against PAO1 in the nematode Caenorhabditis elegans slow killing assay. The results of these studies elucidated the capability of these compounds to reduce the virulence of the wild-type PAO1, highlighting the roles of pel and psl EPS biosynthesis genes as promising tools for the development of antivirulence drugs.

7. Thiazoles as Pilicides

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Targeting the adhesion of bacteria to host tissue is an emerging antivirulence strategy to counteract the resistance toward antibiotics because this process is necessary for pathogenesis, but it is not fundamental for the microbial growth and viability. (112)
The bacterial cell envelope can be extremely different among bacterial species presenting lipids, proteins, and exopolysaccharides, as well as fimbrial and nonfimbrial structures.
In Gram-negative pathogens, filamentous protein extensions, known as pili, are important virulence factors involved in nonspecific initial adhesion to abiotic surface and tissue colonization. (113)
Among the Gram-negative bacteria, uropathogenic E. coli (UPEC) is the primary cause of urinary tract infections (UTIs), which are among the most frequent diseases in community and hospital environments. (114) In E. coli, pilus assembly is mediated by the chaperone/usher pathway (CUP pili), which is granted as a valuable target for the study of antivirulence agents able to prevent E. coli adhesion and biofilm formation.
A series of dihydrothiazole derivatives 50 (Figure 18) is described as pilicides able to bind the PapD–PapH chaperone–subunit complex, as revealed by X-ray crystallographic studies. (115) Many of the C-2 aryl and heteroaryl-substituted derivatives of this class efficiently inhibited E. coli UTI89 biofilm formation, showing IC50s in the micromolar range, in particular the benzyl substituted displayed the highest potency in the biofilm inhibition evaluation assay with an IC50 of 7 μM. The introduction of a phenyl group at C-2 position significantly improved the inhibitory activity of pilus formation due to the establishment of additional hydrophobic interactions with the chaperone shallow pocket formed by the residues Pro30, Leu32, Ile93, and Pro95. The presence of a C-2 phenyl substituent caused a conformational change in the side chain of Leu32 that generated a surface pocket capable of accommodating it.

Figure 18

Figure 18. Chemical structures of compounds 50 and nitaxozanide (51).

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Recent studies described the pilicides activity of the nitrothiazolyl-salicylamide nitazoxanide (51) (NTZ) (Figure 18), which is known for its therapeutic properties toward intestinal diseases including giardiasis and cryptosporidiosis. (116) NTZ inhibits pili biogenesis by affecting CU pathways. In particular, it was observed that the mode of action is associated with a specific interference with proper maturation of the usher protein in the bacterial outer membrane (OM).

8. Compounds with Synergistic Effect in Association with Conventional Antibiotics

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Resistance-nodulation division (RND)-type efflux pumps, causing the cellular extrusion of a number of antibiotics, such as β-lactams and β-lactamase inhibitors, fluoroquinolones, tetracyclines, and oxizolidines, play a key role in the MDR phenotype in Gram-negative pathogens.
Structurally RND pumps are formed by an integral membrane pump protein (AcrB), an OM channel (TolC) and a protein adapter (AcrA) (Figure 19). (117)

Figure 19

Figure 19. (A) RND efflux pump structure: integral membrane pump protein (AcrB), an outer membrane (OM) channel protein (TolC), and a periplasmic membrane fusion protein (AcrA). (117) (B) AcrB structure.

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Compounds that are able to inhibit efflux pumps are strongly required for restoring or increasing the antimicrobial activity of currently used antibiotics.
The design of new efflux pumps inhibitors (EPI) to overcome the MDR in Gram-negative pathogens have to take into account the structural features of both bacterial OM and RND. Whereas the penetration of the OM is favored for zwitterionic or hydrophilic molecules, contrarily, the binding with RND pumps needs a hydrophobic structure.
Despite many efforts in this field and the development of many EPIs, none of these compounds has reached the clinic to date.
A set of 2-substituted benzothiazoles 52a–n (Table 17) was able to rescue the antibacterial effect of ciprofloxacin (15) (CIP) in the AcrAB-TolC overexpressor E. coli AG102 mutant. (118)
Table 17. Chemical Structures and Observed MIC Values against the AcrAB-TolC Efflux Pump Overexpressor E. coli AG102 Strain of 2-Substituted Benzothiazoles 52a–n
compd R X Y MIC (μg/mL)a E. coli AG102 combination with CIP MIC (μg/mL)b
ciprofloxacin (15, CIP)       0.125    
52a H     256 CIP + 24a 0.03
52b OCH2(CH2)C2H5     64 CIP + 24b 0.5
52c C2H5     128 CIP + 24c 0.016
52d OCH3   CH2 256 CIP + 24d 0.008
52e F   CH2 128 CIP + 24e 0.03
52f CH3   CH2 512 CIP + 24f 0.004
52g H   CH2 256 CIP + 24g 0.125
52h F CH2 CH2 256 CIP + 24h 0.03
52i F CH2   128 CIP + 24i 0.03
52j Br CH2   128 CIP + 24j 0.03
52k NO2 CH2   128 CIP + 24k 0.06
52l C2H5 CH2   64 CIP + 24l 0.06
52m H CH2   256 CIP + 24m 0.016
52n H   C2H4 512 CIP + 24n 0.004
a

Observed MIC values of compounds tested alone.

b

Observed MIC values of CIP tested in combination with each compound.

Derivatives 52f and 52n showed a 10-fold reduction in the MIC value of CIP against E. coli AG102 strain, while 52d reduced it by about 8-fold (Table 17). These derivatives did not show intrinsic antibacterial activity but displayed a significant synergistic effect in combination with CIP against E. coli AG102. Compounds 52f and 52n associated with CIP indeed exhibited the highest antibacterial activity eliciting MIC values of 0.004 μg/mL.
Results of docking studies performed on 52, which have low molecular weights (in the range 330–402), in the crystal structure of the binding monomer T of AcrB (PDB 2DRD) were in agreement with the data obtained from the cellular assay. In fact, the major affinity toward the binding site of the monomer AcrB was shown by the derivatives 52d, 52f, and 52n, which displayed stronger binding interactions energies in comparison with CIP. All results suggested a mechanism of inhibition of AcrB by binding to the phenylalanine-rich region in the distal pocket. In particular, derivatives 52d and 52f docking poses showed a hydrogen bond with Asn274 and a π–π interaction with Phe178 and Tyr772, respectively. However, compound 52n showed a π–π interaction with Tyr772 and two π–cation interactions with Lys292 (Figure 20). The three compounds bound to the same region in the deep distal binding pocket of the T monomer, inhibiting or blocking CIP binding site. Studies of the binding energies of 52d, 52f, and 52n showed, for derivatives 52f and 52n, stronger binding energies than CIP, while for 52d, a lower energy was found. Therefore, two different mechanisms were hypothesized: a competitive inhibition of the CIP binding site for compounds 52f and 52n and an uncompetitive inhibition for 52d.

Figure 20

Figure 20. Schematic representation of docking poses of compounds 52d, 52f, and 52n in the AcrB binding monomer crystal structure (PDB 2DRD). Hydrogen bonds in green, a π–π interactions in blue, and π–cation interactions in red.

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AcrB is a protein of 1049 amino acids organized in three monomers or protomers characterized by different conformations: (i) loose (L), which is the access protomer, (ii) tight (T), which is the binding protomer, and (iii) open (O), which works as extrusion protomer. Crystallographic studies of AcrB with its substrates minocycline (53) and doxorubicin (54) highlighted that only one protomer is involved in the binding with the ligand and it depends by the molecular mass of the substrate. Compounds with low molecular mass, including minocycline (53) and doxorubicin (54), were bound in the T protomer in the phenylalanine-rich region. Conversely, compounds with high molecular mass, such as rifampicin (55) and erythromycin (56), docked the L monomer. The two different binding pockets are known as distal and proximal, respectively (Figure 21).

Figure 21

Figure 21. Chemical structures of minocycline (53), doxorubicin (54), rifampicin (55), and erythromycin (56).

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Most recently, another class of thiazole derivatives endowed with interesting synergistic effect with conventional antibiotics was discovered within a study aimed to obtain new sulfonamide derivatives as dihydropteroate synthase (DPHS) inhibitors. (119)
The antibacterial activity of sulfonamides is due to the modulation of the folate pathway by inhibiting DPHS, which drives the formation of dihydropteroate (DHPt) from p-aminobenzoic acid (PABA) and 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPPP).
Compounds 57a–c and 58a,b (Figure 22) were active against all the tested strains, i.e., B. cerus, S. aureus, E. coli, and P. aeruginosa and showed a peculiar selectivity toward the Gram-negative E. coli, with MIC values in the range of 3.1–12.5 μg/mL. In particular, when compared with the reference drugs, the thiazole derivative 58a (MIC, 3.1 μg/mL) was equipotent to sulfamethoxazole (59) (Figure 22) and two times more potent than chloramphenicol (60) (MIC, 6.2 μg/mL) (Figure 22) against E. coli and P. aeruginosa. Further studies evaluated the synergistic effect of the new compounds in terms of fractional inhibitory concentration (FIC) through a combination study with sulfamethoxazole (59) and chloramphenicol (60) against all four bacterial strains. FIC values of 0.24 and 0.25 were observed in all tested strains. The compounds used in association with sulfamethoxazole (59) and chloramphenicol (60) demonstrated their ability to diminish the MIC of the antibiotic of 8-fold against E. coli. Remarkably, the combined MIC value (0.1953 μg/mL) of compound 58b with chloramphenicol (60) was 32-fold lower than the original MIC of 6.2 μg/mL. Such results highlighted the value of these compounds as efficacious adjuvants in an antibacterial combination approach.

Figure 22

Figure 22. Chemical structures of compounds 57a–c, 58a,b, sulfamethoxazole (59), and chloramphenicol (60).

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9. Antibacterial Activity of Thiazole Derivatives with Unknown Mechanism of Action

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9.1. Thiazoles

Very recently, new thiazole-based compounds, 61 (120) (Figure 23) and 62a–g (Table 18), (121) were synthesized and tested for their antibacterial activity. The derivative 61 showed MIC values ranging from 78.1 to 396 μg/mL against the Gram-positive S. aureus and Bacillus subtilis and against the Gram-negative E. coli and Proteus vulgaris pathogens, resulting in being more efficacious toward S. aureus. The presence of p-tolyl and ethoxycarbonyl groups at positions 1 and 3, respectively, of the pyrazole ring was advantageous for the antibacterial activity of this class of compounds.

Figure 23

Figure 23. Chemical structure of compound 61.

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Table 18. Chemical Structures and Antibacterial Activities of Compounds 62a,b
    MIC values (μg/mL)
compd R S. aureus B. subtilis P. aeruginosa K. pneumoniae
62a NO2 25 25 6.25 12.5
62b F 50 50 25 25
chloramphenicol (60)   6.25 6.25 6.25 12.5
For the thiazole series 62, the antibacterial activity against S. aureus, B. subtilis, P. aeruginosa, and K. pneumoniae was positively influenced by the presence of electron withdrawing groups on the phenyl ring, as it has been confirmed by MIC values in the range of 6.25–50 μg/mL for the compounds 62a,b (bearing a nitro group or fluorine atom, respectively). SAR studies also highlighted the key role of the thiazole ring for the antibacterial activity. The in vitro antimicrobial studies confirmed the compound 62a exhibit selective activity toward P. aeruginosa and K. pneumonia, proving to be equipotent to the standard drug chloramphenicol (60) (Table 18).

9.2. Benzothiazoles

To unravel the SAR of the 2-mercaptobenzothiazole scaffold for the development of antibacterial agents, Franchini et al. studied if the replacement of the hydrogen at the 6-position of the heterocyclic moiety with groups able to form electronic and electrostatic interactions that could be advantageous for the biological properties.
With this purpose, a series of 2-mercaptobenzothiazole derivatives 63 (Table 19) was synthesized and tested for their antibacterial activity against Gram-positive (S. aureus, Bacillus cereus, B. subtilis, E. faecalis) and Gram-negative (E. coli, A. baumannii, K. pneumoniae, P. aeruginosa) pathogens. Among the new compounds, derivatives 63a,b were the most active; in particular, they showed the highest antibacterial activity against S. aureus ATCC 29213 bacteria strain, eliciting MIC values of 3.12 and 12.5 μg/mL. Additionally, compounds 63a,b proved to be active also against the resistant, overexpressing NorA efflux pump, S. aureus bacterial strains, demonstrating that they manage to overcome this mechanism of antibiotic resistance. (122)
Table 19. Chemical Structures of Compounds 63a,b, 64a–e, and 65a–c
compd R R1 MIC (μg/mL) compd R R1 MIC (μg/mL)
63a CF3   3.12a 64d NH3+Cl– H 8b
63b NO2   12.5a 64e NH3+Cl– NH3+Cl– 16b
64a H NO2 16b 65a 2,4-diOH-Ph   20c
64b H NH2 8b 65b 2,4-diOCH3-Ph   22c
64c H NH3+Cl– 16b 65c 3,4,5- triOH-Ph   18c
a

The in vitro minimal inhibitory concentrations (MICs) were determined against S. aureus ATCC 29213 bacterial strain.

b

The in vitro minimal inhibitory concentrations (MICs) were determined against E. faecalis bacteria strain.

c

The in vitro minimal inhibitory concentrations (MICs) were determined against methicillin-resistant S. aureus (MRSA090) bacterial strain.

Other thiazole derivatives described for their antibacterial activity were the 2-benzothiazolyl benzo[b]thieno-2-carboxamides 64a–e (Table 19), which showed interesting activity against E. faecalis with MIC values in the range 8–16 μg/mL, (123) and benzo[d]thiazole-hydrazones analogues 65a–c (Table 19), (124) in which the electron donating groups, such as OH or OCH3, play a pivotal role in the antibacterial activity, as it has been confirmed by good MIC values in the range 18–22 μg/mL, obtained for the compounds 65a–c against methicillin-resistant S. aureus (MRSA090) bacterial strain.
Also, benzothiazole complexes are reported as potent antibacterial agents. Recently, the antimicrobial properties of two cationic Au(I) complexes derived from aryl-benzothiazoles: [(PPh3)Au(pbt)](OTf) 66 and [(PPh3)Au(qbt)](OTf) 67 (pbt = 2-(pyridyl)benzothiazole, qbt = (quinolyl)benzothiazole, and OTf = trifluoromethanesulfonate anion) were described (Figure 24). (125) Complexes 66 and 67 showed strong antibacterial effects against the Gram negative bacteria A. baumannii and P. aeruginosa in a skin and soft tissue infection (SSTI) model.

Figure 24

Figure 24. Chemical structures of compounds 66 and 67.

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Through this model, the gradual penetration of bacteria deeper into the skin was evaluated using a two-layer agar system in which there is a layer of dispersed bacterial cells on the top and a nutrient-rich bottom layer. The gradient determines the slow migration of the bacteria from the top layer to the bottom layer, imitating the infectious process of the skin.
Complexes 66 and 67 were able to migrate and inhibit the infections from A. baumannii and P. aeruginosa more potently with respect to the neutral starting material PPh3AuCl. Results highlighted that the bactericidal effect was mainly due to the interaction between the cationic gold complexes and the bacterial cell membrane. Additionally, they are able to generate the reactive species Ph3PAu+ inside of the bacterial cell, which binds many biomolecules crucial for bacterial viability. Unfortunately, no information is available on their effects on the onset of antibiotic resistance.
A similar approach was used to obtain a class of imidazo[2,1-b]benzothiazolyl triazolium analogues, 68a–r and 69a–f (Table 20), which were tested in vitro for evaluating their antibacterial activity against the Gram-positive pathogens MRSA, S. aureus, B. subtilis, and M. luteus and the Gram-negative E. coli, Shigella dysenteriae, P. aeruginosa, S. typhi, and B. proteus. Some of them acted as potent antimicrobial agents eliciting MIC values in the low micromolar range. (126) Of note, the unsubtituted derivatives 68a–i showed higher potency compared to the compounds bearing the ethoxy group at R1 position (68j–r). The series 69 proved to be less effective than 68, suggesting a detrimental effect of the alkyl chain for the antibacterial activity. It was observed that the biological activity in this series was influenced by the chain length, in fact, the pentyl derivatives 69a and 69b showed the highest potency, exhibiting in the case of compound 69b a MIC value of 8 μg/mL against S. aureus and B. proteus and of 2 μg/mL against M. luteus and S. dysenteriae. The presence of longer chains led to a decrease in the growth inhibition. Among the more potent series, 68 compounds substituted with two halogen atoms were more effective than the monosubstituted, in particular, the dichloro derivatives 68g, 68h, and 68q proved to me more potent than chloromycin (12), eliciting MIC values against P. aeruginosa of 8, 16, and 4 μg/mL, respectively. Interaction studies of calf thymus DNA with the most active compound of the series 68q elucidated a possible mechanism of action involving the intercalation into the DNA and the consequent block of replication.
Table 20. Chemical Structures of Compounds 68a–r and 69a–f
compd n R1 R2 R3 R4 compd n R1 R2 R3 R4
68a   H Cl H H 68m   OEt F H H
68b   H H Cl H 68n   OEt H F H
68c   H H H Cl 68o   OEt H H F
68d   H F H H 68p   OEt Cl H Cl
68e   H H F H 68q   OEt H Cl Cl
68f   H H H F 68r   OEt H H NO2
68g   H Cl H Cl 69a 4 H      
68h   H H Cl Cl 69b 5 H      
68i   H H H NO2 69c 6 H      
68j   OEt Cl H H 69d 4 OEt      
68k   OEt H Cl H 69e 5 OEt      
68l   OEt H H Cl 69f 6 OEt      

9.3. 4-Thiazolidinone Derivatives

A series of 4-thiazolidinone derivatives of the type 70 (Figure 25), bearing thiazole, thiazolidinone, and adamantane scaffolds, was synthesized and evaluated for the antibacterial activity against a panel of Gram-positive and Gram-negative bacteria including B. cereus (clinical isolate), M. flavus (ATCC 10240), L. monocytogenes (NCTC 7973), S. aureus (ATCC 6538), E. coli (ATCC 35210), P. aeruginosa (ATCC 27853), S. typhimurium (ATCC 13311), and Proteus mirabilis (human isolate). (127) All of these compounds elicited a significant antibacterial activity against all the tested strains showing MIC values ranging from 5.01 to 20.8 μg/mL. Determination of MBC, which was almost 2-fold higher than the corresponding MIC, elucidated a bacteriostatic mechanism.

Figure 25

Figure 25. Chemical structures of compounds 70.

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The introduction of arylidene moieties in the thiazolidinone ring improved significantly the antimicrobial activity, and various substitutions on this nucleus were well tolerated. However, despite the excellent antibacterial activity described for derivatives 70 (Figure 25), two critical issues must be taken into account and need further studies: the knowledge of the mechanism of action and the possibility that they were PAINS compounds because of their potential to be Michael acceptor.
Other 4-thiazolidinone derivatives reported for their antibacterial activity were derivatives 71a–l (Table 21), which showed significant properties against the Gram-negative P. aeruginosa and E. coli, with MIC values ranging from 1.56 to 12.5 μg/mL, and against the Gram-positive S. aureus and B. subtilis, with MIC values between 1.56 and 6.25 μg/mL. (128) The highest activity was obtained for derivatives with electron withdrawing group, including a bromine atom or nitro group on the aromatic ring.
Table 21. Chemical Structures and Antibacterial Activities of Compounds 71a–l
      MIC values (μg/mL)
compd Ar Ar1 E. coli MTCC 40 P. aeruginosa MTCC 2453 S. aureus MTCC 121 B. subtilis MTCC 96
71a Ph Ph 6.25 6.25 6.25 3.12
71b Ph 3-NO2-Ph 6.25 3.12 3.12 1.56
71c Ph 4-Cl-Ph 3.12 12.5 3.12 6.25
71d Ph 3-Br-Ph 12.5 6.25 3.12 6.25
71e Ph 3-OCH3-Ph 6.25 6.25 6.25 1.56
71f 3-Br-Ph Ph 6.25 3.12 3.12 3.12
71g 3-Br-Ph 3-NO2-Ph 3.12 1.56 1.56 1.56
71h 3-Br-Ph 4-Cl-Ph 12.5 6.25 6.25 6.25
71i 3-Br-Ph 3-Br-Ph 6.25 6.25 3.12 3.12
71j 3-Br-Ph 4-OCH3-Ph 1.56 12.5 3.12 1.56
71k 3-F-Ph Ph 6.25 12.5 6.25 3.12
71l 3-F-Ph 3-NO2-Ph 12.5 3.12 6.25 6.25
Compounds 72a–c (Table 22), containing the 4-thiazolidinone scaffold, displayed promising antimicrobial activity against the planktonic form as well as the biofilm of K. planticola, which is a main responsible cause of nosocomial infections of urinary tract. (129) These derivatives elicited MIC and MBC values of 3.9 and 15.6 μg/mL, respectively. Additionally, they were able to inhibit K. planticola biofilm formation with BIC50 ranging from 20.28 to 20.79 μg/mL. The exact target of these molecules is not known, and consequently, the role of the thiazolidinone scaffold for the biological activity is not clear. However, modification on this nucleus influenced the antimicrobial properties. In particular, the presence of electron withdrawing substituents on the thiazolidinone scaffold was advantageous for the antibacterial activity, whereas the substitution of the phenyl ring with different heterocycles caused the loss of this activity. These observations suggest the involvement of the thiazolidinone ring in driving the biological activity.
Table 22. Chemical Structures and Antibacterial Activities of Compounds 72a–c
    K. planticola MTCC 530
compd R MIC (μg/mL) MBC (μg/mL) BIC (μg/mL)
72a 4-CF3-Ph 3.9 15.6 20.28
72b 3-CF3-Ph 3.9 15.6 20.72
72c 4-OCF3-Ph 3.9 15.6 20.79
Pitta and collaborators combined the three bioactive scaffolds thiazole, adamantane, and 4-thiazolidinone in order to obtain a new series of derivatives 73 (Table 23) with a remarkable antibacterial activity against a wide spectrum of Gram-positive and Gram-negative bacteria. (130)
Table 23. Chemical Structures and Antibacterial Activity of Compounds 73a–j
    MIC values (μg/mL)
compd R B. cereus M. flavus S. aureus L. monocytogenes E. coli E. coclae P. aeruginosa S. typhimurium
73a 2-Cl 13.2 19.4 26.9 7.0 26.9 13.2 26.9 26.9
73b 3-Cl 7.0 26.9 13.2 26.9 26.9 26.9 29.6 13.2
73c 4-Cl 7.0 13.2 7.0 26.9 26.9 26.9 7.0 7.0
73d 2,3-diCl 14.2 14.2 4.18 29.0 29.0 14.2 7.1 7.1
73e 2,6-diCl 200 100 200 200 100 200 200 100
73f 3-F 124 12.7 124 6.33 6.33 12.7 3.7 3.7
73g 4-Br 47 100 200 200 100 9.5 200 100
73h 4-NO2 7.2 27 13.5 27 37.5 13.5 13.5 13.5
73i 4-OCH3 6.9 26.6 13.0 26.6 13.0 13 13.0 13.0
73j 2,5-diOCH3 100 100 200 200 100 100 200 100
These compounds were more potent than the references drugs ampicillin and streptomycin, showing MIC values ranging from 3.7 to 200 μg/mL against the Gram-positive Bacillus cereus (clinical isolate), Micrococcus flavus (ATCC 10240), S. aureus (ATCC 6538), and Listeria monocytogenes (NCTC 7973), and the Gram-negative E. coli (ATCC 35210), Enterobacter cloacae (human isolate), P. aeruginosa (ATCC 27853), and Salmonella typhimurium (ATCC 13311).
The highest antibacterial activity was found for compound 73d, which elicited MIC values in the range of 4.18–29 μg/mL against all the tested strains. Notably, the position of the chlorine atom on the phenyl ring did not influence the biological activity of this class of compounds, whereas the introduction of a second chlorine was advantageous for the activity in the case of 2,3-disubstituted compounds but was detrimental in the case of the 2,6-disubstituted derivative. The presence of a fluorine atom at position 4 in the phenyl ring led to an improvement in the antimicrobial activity against all the bacterial strains except for B. cereus and S. aureus.
To investigate the potential mechanism of action involving the enzyme MurB, the most active compounds 73d and 73e were docked in the S. aureus MurB active site (PDB 1HSK).
Compound 73d (R-isomer) formed hydrogen bond contacts with the residues Gly249 and Arg242, and it was also involved in a Cl−π interaction with Phe274 of the active site. The phenyl ring of the 2,3-dichlorophenyl moiety is proposed to be involved in hydrophobic interactions with the amino acids Val239 and Gly273 and in π–π interaction with Phe274. Although in silico studies suggested a good affinity between derivatives 73 and MurB, no in vitro experiments on the enzyme have been carried out to validate this hypothesis.
A new series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivatives 74a–e (Table 24) was created and tested in vitro for the antibacterial activity and in silico for the MurB affinity. (131) The highest activity was observed for derivative 74a, which showed MIC values of 8 μg/mL against S. aureus and 16 μg/mL against E. faecalis, B. subtilis, and E. coli. This was attributed to the good lipophilic features of this compound (log P value of 3.84), which makes possible the crossing of the lipid coat of bacteria. SAR studies highlighted that the presence of a methoxy group at the R position and fluorine, nitro, methoxy, and methyl at the R1 are advantageous for the antibacterial activity of these compounds.
Table 24. Chemical Structures and Antibacterial Activity of Compounds 74a–ea
    MIC values (μg/mL)
compd R S. aureus E. faecalis B. subtilis E. coli
74a Cl 8 16 16 16
74b F 128 ND ND 64
74c NO2 16 ND ND 32
74d OCH3 128 ND ND 6
74e CH3 64 ND ND 32
a

ND = not determined.

Studies of molecular modeling with 74a revealed a good affinity toward the enzyme MurB with a binding energy of −12.18234 kcal/mol, but also in this case, the computational results are not supported by enzymatic assays.
A series of 4-thiazolidinone derivatives 75a–e (Table 25) was described for their potent antimicrobial activity against S. aureus, B. subtilis, and E. coli, showing comparable potency to norfloxacin used as reference drug. (132) The highest activities were elicited by compounds 75b and 75d, against the Gram-negative E. coli pathogen, with a MIC value of 3.07 μg/mL, and against S. aureus, with a MIC value of 6.51 μg/mL, respectively. Against Gram-positive B. subtilis pathogen, the derivative 75a showed the best MIC value of 6.24 mg/mL. The new compounds showed a bacteriostatic activity because their MBC values were 3-fold higher than the MICs. The introduction of electron withdrawing groups increased the antibacterial activity of this class of compounds against S. aureus and B. subtilis, while electron donating groups were advantageous for the activity against E. coli.
Table 25. Chemical Structures and Antibacterial Activities of the 4-Thiazolidinones 75a–e
    MIC (μg/mL)
compd R S. aureus B. subtilis E. coli
75a 2-Cl 12.5 6.24 6.24
75b 4-Br 6.51 47.8 12.16
75c 3-NO2 25.23 12.41 25.23
75d 4-N(CH3CH2)2 12.37 12.37 3.07
75e 4-CH3 12.56 12.56 12.56
Recently, a sulfurated analogue of thiazolidinone compounds, the 1,3-thiazolidin-2-thione 76 (Figure 26), was found to act as an antibacterial agent equipotent to chloramphenicol (60) against S aureus, with a MIC value of 3.12 μg/mL, and with a significant activity also against Bacillus thuringiensis, with a MIC value of 6.25 μg/mL. (133) Despite this interesting activity, thiazole derivative 76 did not demonstrate a significant increase in activity with respect to the pyridine analogue previously reported. Conversely, the authors observed a decrease in the activity against the Gram-negative pathogens was. Therefore, in this case, the presence of the thiazole scaffold seems not relevant for the antibacterial activity.

Figure 26

Figure 26. Chemical structure of 76.

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10. Conclusions and Future Directions

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There is a need of a prompt intervention to face the global emergency of antibiotic resistance.
In addition to the rational use of the conventional antibiotics, which requires coherent strategy in human, animal, plant, and environmental health (One Health strategy), in order to preserve their efficacy in treating infectious diseases, other actions, such as development of new antimicrobial agents, are needed.
In the past decade, many thiazoles and benzothiazoles were described for their interesting antibacterial activity, in many cases also against MDR strains. One of the most significant feature of this class of compounds consists in their ability to interfere with diverse bacterial targets, including DNA gyrase, topoisomerase IV, biofilm formation, cell wall permeability, and tryptophanyl-tRNA synthetase. Consequently, they proved to be active against a broad spectrum of relevant Gram-positive and Gram-negative pathogens, with MIC values in the low micromolar range. Regarding the mechanisms of action, the most investigated is the inhibition of type II topoisomerases. In particular, the benzothiazoles 3a,b potently inhibited in vitro E. coli DNA gyrase and topoisomerase IV, with IC50 in the range 0.0033–0.046 μg/mL, eliciting MIC values between 0.008 to 0.06 μg/mL against S. pneumoniae, S. epidermidis, and S. pyogenes. In addition, because DNA gyrase is a crucial enzyme for bacterial viability, its inhibition could cause the development of antibiotic resistance strains, as was observed for the fluoroquinolone antibiotic class. Therefore, particularly relevant has been the study performed for evaluating their ability to induce resistance in terms of FoR, which established that these benzothiazole ethyl urea derivatives had a low capability to determine drug resistance, then they could be considered interesting lead compounds worthy of being developed.
Topoisomerases can be considered valuable targets for drug discovery as they are conserved across numerous bacterial species, so a broad spectrum of activity should be feasible. Moreover, in the past decade, new insights have been obtained in the molecular mechanisms of DNA gyrase and topoisomerase IV inhibition, the individuation of the structural features required for the interaction with the binding site and the factors responsible for the resistance development. This knowledge allowed identifying clinical drug candidates such as AZD5099 (19), which proved to be efficacious in different in vivo models for the treatment of nosocomial lung and skin infections caused by relevant Gram-positive pathogens.
Importantly, AZD5099 (19) showed FoR lower than the detection limit of 9.6 × 10–10 and impressive selectivity against the bacterial topoisomerase II compared to the human enzyme.
The modulation of the bacterial cell wall synthesis and permeability still remains a good target for the development of innovative antimicrobials, and many thiazoles are able to inhibit enzymes involved in these processes. However, assays to investigate the FoR values should be carried out because targets responsible for the integrity of the cell wall are needed for the bacterial viability, consequently the evolution of antibiotic resistance is unavoidable. Particularly relevant the data observed for the cephalosporin Cefiderocol, whose effectiveness and safety has been demonstrated for the treatment of cUTI and acute uncomplicated pyelonephritis in a clinical phase II trial.
An important aspect to take into consideration during the design of new antibacterial compounds bearing the thiazole scaffold is the classification of 14 subclasses of 2-aminothiazoles (2-ATs) as PAINS. (134) PAINS compounds are promiscuous molecules that give multiple positive results, often not reliable, to different biological assays, and for this reason they should be removed from screening libraries and biological assay. (135,136) There are different reasons for their promiscuous behavior, including their photoreactivity, the presence of impurities generated by bromomethyl ketones often used as chemical precursors in their preparation, and their chemical feature as thiol-reactive species. (137) On the other side, it must be considered that the biological and therapeutic value of 2-ATs is widely recognized because many marketed drugs, including antibiotics like cefepime, cefetamet, cefoselis, cefotaxime, cefotiam, cefpodoxime, cefpirome ceftazidime, ceftibuten, and ceftriaxone are bearing this fragment in their structure.
Also, for the thiazolidinone derivatives, already known for their interesting pharmacological profile, it is important to consider, in the design of new antibacterial agents, their potential as PAINS. Classes such as 5-ene-4-thiazolidinones, indeed, often showed good activities within a range of different assays and against numerous proteins. Therefore, studies to exclude that the results are not related to the nature of Michael acceptors are needed.
It is important to consider that the possibility of being Michael acceptors is not necessarily associated with the behavior as PAINS compounds and it is often not confirmed experimentally under physiological conditions. (138) Additionally, advantageous toxicological profile of several classes of 4-thiazolidinones strongly encourage their development and study as new drugs. (139)
The thiazole derivatives, which hit virulence factors, but do not interfere with the microbial growth, could be considered “evolution proof” and for sure worthy to be developed as antivirulence agents. Among them, the inhibitors of biofilm formation, compounds 44 and 46, that potently inhibited biofilm formation of relevant pathogens without affecting their viability, can be considered deserving for the design of novel antivirulence compounds.

Author Information

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  • Corresponding Author
  • Authors
    • Stella Cascioferro - Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy;  Orcidhttp://orcid.org/0000-0002-4725-1881
    • Barbara Parrino - Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
    • Daniela Carbone - Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
    • Domenico Schillaci - Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
    • Elisa Giovannetti - Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, DeBoelelaan 1117, 1081HV, Amsterdam, The Netherlands;  Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, via Giovannini 13, 56017 San Giuliano Terme, Pisa, Italy
    • Girolamo Cirrincione - Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
  • Notes
    The authors declare no competing financial interest.

Biographies

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Stella Cascioferro

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Stella Cascioferro graduated in Pharmacy with honors in 1999, and she got her Ph.D. in Medicinal Chemistry in 2004 at the University of Palermo. In 2004, she joined the Physical and Theoretical Chemistry Laboratory at the University of Oxford as part of the group led by Professor Graham Richards. Her research interests include the design, synthesis, and biological evaluation of heterocyclic compounds as antitumoral and antinfective agents. Currently, she is researcher at the University of Palermo, Italy. She is the author of 58 scientific papers published in peer reviewed international journals of medicinal chemistry.

Barbara Parrino

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Barbara Parrino graduated in Medicinal Chemistry and Technology at the University of Palermo with full marks with honors in 2007. She got her Ph.D. in Pharmaceutical Sciences in March 2012, during which she was a Ph.D. visiting student at Semmelweiss University and at the University of Nottingham, and for which she received the “Doctor Europaeus” label. On September 2012, she was awarded the P. Ehrlich MedChem Euro-PhD Network Certificate. In 2015 she was recipient of the Medicinal Chemistry Division of the Italian Chemical Society Prize. From November 2012 to October 2017, she was a Postdoc Research fellow at the University of Palermo. Currently, she is researcher at the University of Palermo and author of 51 papers and one Italian patent.

Daniela Carbone

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Daniela Carbone holds a master’s degree in Pharmacy (full marks with honors) from the University of Palermo in 2015. From July to November 2018, she was a Ph.D. visiting student at VU University Medical Center of Amsterdam, and she earned her Ph.D. in Molecular and Biomolecular Sciences, with additional certification of Doctor Europaeus, in February 2019. Since April 2019, she has been a Research fellow at the Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (University of Palermo, Italy). Her current research interests are focused on the medicinal chemistry field, particularly the design, synthesis, and biological evaluation of heterocyclic compounds, analogues of natural marine alkaloids, with antitumor and anti-infective properties.

Domenico Schillaci

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Domenico Schillaci is a microbiologist and is the head of the Laboratory of Microbiology and Biological Assays of the Department of Biological, Chemical, and Pharmaceutical Science and Technology (University of Palermo, Italy). He is the head of, or collaborates with, research projects regarding the discovery of new anti-infective and antibiofilm agents, in particular against staphylococcal biofilms. He concentrates on both synthetic organic compounds and natural products as antimicrobial peptides. He is the author of 91 publications in peer reviewed journals. From 2001 to date, he has been teaching General Microbiology to the students of the School of Pharmacy of the University of Palermo. He has served as a reviewer for several journals in the field of applied microbiology.

Elisa Giovannetti

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Elisa Giovannetti is associate Professor of Pharmacology at the VU University Medical Center, Amsterdam, and Principal Investigator at the Cancer Pharmacology Lab (University of Pisa). She is member of the Steering Committee of the Pharmacology and Molecular Mechanisms (PAMM) group of the EORTC, and her studies are funded by grants from Italian Association for Research against Cancer (AIRC), Netherlands Organization for Scientific Research (NWO), Cancer Center Amsterdam (CCA) Foundation, and Dutch Cancer Society (KWF).

Girolamo Cirrincione

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Girolamo Cirrincione is Emeritus Professor of Medicinal Chemistry at the University of Palermo. He is a member of the Drug Discovery Commettee of the Pharmacology and Molecular Mechanisms (PAMM) Group of the European Organization for Research and Treatment of Cancer, the Italian Chemical Society, where he has been President of the Medicinal Chemistry Division, and the International Society of Heterocyclic Chemistry, where he served as vice president for 2004–2005. He was Pro-rector for Research of the University of Palermo for 2015–2018.

Patrizia Diana

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Patrizia Diana is full Professor of Medicinal Chemistry at the University of Palermo. She is currently coordinator of the Ph.D. course of Molecular and Biomolecular Sciences and of the Medicinal and Biological Section of the Department of Science and Technology: Chemical, Biological and Pharmaceutical (STEBICEF) of the University of Palermo. She is a member of the Italian Chemical Society and International Society of Heterocyclic Chemistry and of the PAMM group of the ORTC.

Acknowledgments

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Figure 3 is a reproduction of Figure 8 from ref (25), and for this reason we thank the authors.

Abbreviations Used

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AMR

antibiotic-resistance
2-ATs

2-aminothiazoles
AUC

area under the curve
CLSM

confocal laser scanning microscope
CIA

critical important antimicrobials
CIP

ciprofloxacin
CUP

chaperone/usher pathway
DHPPP

6-hydroxymethyl-7,8-dihydropterin-pyrophosphate
DHPt

dihydropteroate
DPHS

dihydropteroate synthase
EPI

efflux pumps inhibitors
EPS

extracellular polymeric substances
FBLG

fragment-based lead generation approach
FIC

fractional inhibitory concentration
FnBPA

fibronectin binding protein A
FoRs

spontaneous frequencies of resistance
HTS

high-throughput screening
LPS

lipopolysaccharide
MIC

minimum inhibitory concentrations
MurB

uridine diphosphate-UDP-N-acetylenolpyruvylglucosamine reductase
NTZ

nitazoxanide
OM

outer membrane
OTf

trifluoromethanesulfonate anion
PABA

p-aminobenzoic acid
pbt

2-(pyridyl)benzothiazole
PAINS

pan assay interference compound
PK

pharmacokinetic
qbt

(quinolyl)benzothiazole
QS

quorum sensing
SEM

scanning electron microscope
SrtA

sortase A
TrpRS

tryptophanyl-tRNA synthetase
UPEC

uropathogenic Escherichia coli
UTIs

urinary tract infections

References

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This article references 139 other publications.

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    Antimicrobial resistance (AMR) is one of the most serious global public health threats in this century. The first World Health Organization (WHO) Global report on surveillance of AMR, published in April 2014, collected for the first time data from national and international surveillance networks, showing the extent of this phenomenon in many parts of the world and also the presence of large gaps in the existing surveillance. In this review, we focus on antibacterial resistance (ABR), which represents at the moment the major problem, both for the high rates of resistance observed in bacteria that cause common infections and for the complexity of the consequences of ABR. We describe the health and economic impact of ABR, the principal risk factors for its emergence and, in particular, we illustrate the highlights of four antibiotic-resistant pathogens of global concern - Staphylococcus aureus, Klebsiella pneumoniae, non-typhoidal Salmonella and Mycobacterium tuberculosis - for whom we report resistance data worldwide. Measures to control the emergence and the spread of ABR are presented.
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    Sharma, D.; Misba, L.; Khan, A. U. Antibiotics versus Biofilm: An Emerging Battleground in Microbial Communities. Antimicrob. Resist. Infect. Control 2019, 8, 76,  DOI: 10.1186/s13756-019-0533-3
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    Antibiotics versus biofilm: an emerging battleground in microbial communities
    Sharma Divakar; Misba Lama; Khan Asad U
    Antimicrobial resistance and infection control (2019), 8 (), 76 ISSN:.
    Biofilm is a complex structure of microbiome having different bacterial colonies or single type of cells in a group; adhere to the surface. These cells are embedded in extracellular polymeric substances, a matrix which is generally composed of eDNA, proteins and polysaccharides, showed high resistance to antibiotics. It is one of the major causes of infection persistence especially in nosocomial settings through indwelling devices. Quorum sensing plays an important role in regulating the biofilm formation. There are many approaches being used to control infections by suppressing its formation but CRISPR-CAS (gene editing technique) and photo dynamic therapy (PDT) are proposed to be used as therapeutic approaches to subside bacterial biofim infections, especially caused by deadly drug resistant bad bugs.
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  3. 3
    Gebreyohannes, G.; Nyerere, A.; Bii, C.; Sbhatu, D. B. Challenges of Intervention, Treatment, and Antibiotic Resistance of Biofilm-Forming Microorganisms. Heliyon 2019, 5, e02192  DOI: 10.1016/j.heliyon.2019.e02192
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    Chandler, C. I. R. Current Accounts of Antimicrobial Resistance: Stabilisation, Individualisation and Antibiotics as Infrastructure. Palgrave Commun. 2019, 5, 53,  DOI: 10.1057/s41599-019-0263-4
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    de Kraker, M. E. A.; Stewardson, A. J.; Harbarth, S. Will 10 Million People Die a Year Due to Antimicrobial Resistance by 2050?. PLoS Medicine 2016, 13, e1002184  DOI: 10.1371/journal.pmed.1002184
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    Schillaci, D.; Spanò, V.; Parrino, B.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G.; Cascioferro, S. Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms. J. Med. Chem. 2017, 60, 8268– 8297,  DOI: 10.1021/acs.jmedchem.7b00215
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    Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms
    Schillaci, Domenico; Spano, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
    Journal of Medicinal Chemistry (2017), 60 (20), 8268-8297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chem. agents that target the most common mechanisms of antibiotic resistance such as enzymic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here the authors assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. The authors also discuss the potential clin. application of chem. inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymic inhibitors, such as the derivs. of the β-lactamase inhibitor avibactam, are closer to the clinic than other mols. For example, MK-7655, in combination with imipenem, is in clin. development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addn., other mols. targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.
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  7. 7
    Cascioferro, S. The Future of Antibiotic: From the Magic Bullet to the Smart Bullet. J. Microb. Biochem. Technol. 2014, 6, e118  DOI: 10.4172/1948-5948.1000e118
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    Sharma, D.; Bansal, K. K.; Sharma, A.; Pathak, M.; Sharma, P. C. A Brief Literature and Review of Patents on Thiazole Related Derivatives. Curr. Bioact. Compd. 2019, 15, 304– 315,  DOI: 10.2174/1573407214666180827094725
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    A Brief Literature and Review of Patents on Thiazole Related Derivatives
    Sharma, Diksha; Bansal, Kushal K.; Sharma, Archana; Pathak, Meenakshi; Sharma, Prabodh C.
    Current Bioactive Compounds (2019), 15 (3), 304-315CODEN: CBCUBY; ISSN:1573-4072. (Bentham Science Publishers Ltd.)
    Background: Thiazole is widely investigated bioactive scaffold and dynamic tool in medicinal chem. research. Significance of thiazole compds. are well documented as thiazole is an obligatory structure of no. of currently available therapeutics. In spite of that, thiazole derivs. are endowed with myriad biol. activities, such as antiviral, anticancer, antibacterial, antifungal, antimalarial, antiparkinsonian, anti-inflammatory activities and many more. Methods: In recent past, different approaches have been introduced for synthesis of thiazole and related compds. Intrinsic mol. interaction between newly synthesized thiazole compds. and plethora of drug targets/enzymes has rendered discovery of new drug mols. with advances in modes of action. A renewed interest in therapeutic use of thiazole derivs. has been seen among the prospective researchers as exemplified by influx of huge scientific articles and patents. Some important patents of anti-infective and anticancer interest have been addressed appropriately and are presented in tables. Results: This review paper is a contemporary approach on therapeutic/applications of thiazole derivs. by summarizing important patents filed from 2000-2017. The main focus of these patents is on anti-infective and anticancer potential of thiazole based compds. Conclusion: These approaches may provide valuable information for the further design of more active biol. agents through various modifications and derivatizations.
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  9. 9
    Muhammad, Z. A.; Masaret, G. S.; Amin, M. M.; Abdallah, M. A.; Farghaly, T. A. Anti-Inflammatory, Analgesic and Anti-Ulcerogenic Activities of Novel Bis-Thiadiazoles, Bis-Thiazoles and Bis-Formazanes. Med. Chem. 2017, 13, 226– 238,  DOI: 10.2174/1573406412666160920091146
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    Anti-inflammatory, Analgesic and Anti-ulcerogenic Activities of Novel bis-thiadiazoles, bis-thiazoles and bis-formazanes
    Muhammad, Zeinab A.; Masaret, Ghada S.; Amin, Mohamed M.; Abdallah, Magda A.; Farghaly, Thoraya A.
    Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 13 (3), 226-238CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
    Indane-1,3-dione, thiazole, bis-thiazole and thiadiazoles rings are very interested moieties in anti-inflammatory and analgesic drugs. The goal of this work is to synthesize new derivs. of bis-thiazoles and bis-1,3,4- thiadiazoles for the investigation of their anti-inflammatory, anti-ulcerogenic and analgesic activities. 1,1'-(1,2-Phenylene)bis(3-phenylthiourea) (1) reacts with a no. of N-aryl arenecarbohydrazonoyl chlorides 2 to give a series of new bis-1,3,4-thiadiazoles 4. Also, reaction of bisthiosemicarbazone of 1,3-indanedione 6 with another type of hydrazonoyl halides namely, N-aryl-2- oxapropanehydrazonoyl chlorides 7 and ethyl-(N-arylhydrazono)chloroacetate 8 in dioxane under reflux in the presence of triethylamine give the resp. bis-thiazole derivs. 9 and 10, resp. The products 9 and 10 can exist in five and seven tautomeric forms for each one. Their actual tautomeric forms were deduced based on electronic absorption data (UV/Vis spectra). Moreover, a series of novel bis-formazans 12 and 13 have been synthesized by reaction of 1,3-dihydrazono-2,3- dihydro-1H-indene (11) with both hydrazonoyl chlorides 7 and 8. The structure of all the novel products was deduced by elemental anal. and spectral data. In addn., the biol. activity of the newly synthesized compds. was evaluated and the results obtained indicate their potency as anti-inflammatory, anti-ulcerogenic and analgesic agents. In this context, we synthesize new derivs. of bis-thiazoles and bis-1,3,4-thiadiazoles as anti-inflammatory, anti-ulcerogenic and analgesic agents.
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  10. 10
    Hosseinzadeh, N.; Seraj, S.; Bakhshi-Dezffoli, M. E.; Hasani, M.; Khoshneviszadeh, M.; Fallah-Bonekohal, S.; Abdollahi, M.; Foroumadi, A.; Shafiee, A. Synthesis and Antidiabetic Evaluation of Benzenesulfonamide Derivatives. Iran J. Pharm. Res. 2013, 12, 325– 330
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    Synthesis and antidiabetic evaluation of benzenesulfonamide derivatives
    Hosseinzadeh, Nouraddin; Seraj, Soodeh; Bakhshi-Dezffoli, Mohamad Ebrahim; Hasani, Mohammad; Khoshneviszadeh, Mehdi; Fallah-Bonekohal, Saeed; Abdollahi, Mohammad; Foroumadi, Alireza; Shafiee, Abbas
    Iranian Journal of Pharmaceutical Research (2013), 12 (2), 325-330CODEN: IJPRC9; ISSN:1735-0328. (Shaheed Beheshti University of Medical Sciences and Health Services, School of Pharmacy)
    Novel N-(4-phenylthiazol-2-yl)benzenesulfonamides I (R = MeO, X = H; R = MeO, R1 = 2,5-Cl2C6H3; R = MeO, R1 = 2,4,5-Cl3C6H2; R = MeO, R1 = 4-MeOC6H4; R = MeO, R1 = 4-BrC6H4; R = MeO, R1 = 4-MeC6H4; R = MeO, 4-ClC6H4; R = Cl, R1 = 4-MeC6H4) were synthesized and assayed in-vivo to investigate their antidiabetic activities by a streptozotocin-induced model in rat. These derivs. showed considerable biol. efficacy when compared to glibenclamide as a ref. Some of the compds. were effective, amongst which I (R = MeO, R1 = 2,5-Cl2C6H3) showed more prominent activity at 100 mg/Kg p.o.
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  11. 11
    Morigi, R.; Locatelli, A.; Leoni, A.; Rambaldi, M. Recent Patents on Thiazole Derivatives Endowed with Antitumor Activity. Recent Pat. Anti-Cancer Drug Discovery 2015, 10, 280– 297,  DOI: 10.2174/1574892810666150708110432
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    Recent patents on thiazole derivatives endowed with antitumor activity
    Morigi, Rita; Locatelli, Alessandra; Leoni, Alberto; Rambaldi, Mirella
    Recent Patents on Anti-Cancer Drug Discovery (2015), 10 (3), 280-297CODEN: RPADDY; ISSN:1574-8928. (Bentham Science Publishers Ltd.)
    A review. Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chem. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large no. of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compds. useful for the development of new drug mols. It has been divided according to the mol. target and describes the pathways involved in the biol. activities and the structure of the most potent compds., together with the screening results.
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  12. 12
    Pucci, M. J.; Bronson, J. J.; Barrett, J. F.; DenBleyker, K. L.; Discotto, L. F.; Fung-Tomc, J. C.; Ueda, Y. Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics. Antimicrob. Antimicrob. Agents Chemother. 2004, 48, 3697– 3701,  DOI: 10.1128/AAC.48.10.3697-3701.2004
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    12
    Antimicrobial evaluation of nocathiacins, a thiazole peptide class of antibiotics
    Pucci, Michael J.; Bronson, Joanne J.; Barrett, John F.; DenBleyker, Kenneth L.; Discotto, Linda F.; Fung-Tomc, Joan C.; Ueda, Yasutsugu
    Antimicrobial Agents and Chemotherapy (2004), 48 (10), 3697-3701CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-pos. bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compds. against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain addnl. structurally related compds. The MIC assay results of BMS-249524 and two more water-sol. derivs., BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-pos. pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Anal. of killing kinetics revealed that these compds. are bactericidal for S. aureus with at least a 3-log10 redn. of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compds. demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-pos. bacterial pathogens.
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    Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. J. Med. Chem. 2015, 58 (11), 4383– 4438,  DOI: 10.1021/jm501853m
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    A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
    Beno, Brett R.; Yeung, Kap-Sun; Bartberger, Michael D.; Pennington, Lewis D.; Meanwell, Nicholas A.
    Journal of Medicinal Chemistry (2015), 58 (11), 4383-4438CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Electron deficient, bivalent sulfur atoms have two areas of pos. electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramol. interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a mol. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramol. hydrogen-bonding interaction, appears to be underappreciated by the medicinal chem. community. In this Perspective, we discuss the theor. basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and org. synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermol. interactions between ligand C-S σ* orbitals and proteins are illustrated.
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    Meanwell, N. A. A Synopsis of the Properties and Applications of Heteroaromatic Rings in Medicinal Chemistry. Adv. Heterocycl. Chem. 2017, 123, 245– 361,  DOI: 10.1016/bs.aihch.2016.11.002
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    A synopsis of the properties and applications of heteroaromatic rings in medicinal chemistry
    Meanwell, N. A.
    Advances in Heterocyclic Chemistry (2017), 123 (), 245-361CODEN: AHTCAG; ISSN:0065-2725. (Elsevier Inc.)
    A review. Five- and six-membered heteroarom. rings and their benzo-fused homologues are well established as important structural elements in drug design and are well represented in approved drugs. The key properties of these heterocycles that are of interest to medicinal chemists Include lipophilicity, pKa, aromaticity, ionization potential, H-bond acceptor, and H-bond donor (N-H, 0-H, C-H) capability, electron withdrawing effects, dipole values, and bond angles. The judicious and productive application of azoles and azines in drug design requires an understanding of the intrinsic phys. chem. properties of the individual heterocycles and how these interact with substituents. In this article. the key properties of azole and azine heterocycles are summarized followed by a synopsis of applications where some of these factors play a role in drug-target interactions and/or potency.
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    Wolfson, J. S.; Hooper, D. C. The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity in Vitro. Antimicrob. Agents Chemother. 1985, 28, 581– 586,  DOI: 10.1128/AAC.28.4.581
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    The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro
    Wolfson, John S.; Hooper, David C.
    Antimicrobial Agents and Chemotherapy (1985), 28 (4), 581-6CODEN: AMACCQ; ISSN:0066-4804.
    A review, with 79 refs., on fluoroquinolones. The mol. structures, antimicrobial activities, and mechanisms of action and resistance are discussed.
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    Reece, R. J.; Maxwell, A. DNA Gyrase: Structure and Function. Crit. Rev. Biochem. Mol. Biol. 1991, 26, 335– 375,  DOI: 10.3109/10409239109114072
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    DNA gyrase: structure and function
    Reece, Richard J.; Maxwell, Anthony
    Critical Reviews in Biochemistry and Molecular Biology (1991), 26 (3-4), 335-75CODEN: CRBBEJ; ISSN:1040-9238.
    A review, with 246 refs., summarizing current knowledge of DNA gyrase. DNA gyrase is an essential bacterial enzyme that catalyzes the ATP-dependent neg. supercoiling of double-stranded closed-circular DNA. Gyrase belongs to a class of enzymes known as topoisomerases that are involved in the control of topol. transitions of DNA. The mechanism by which gyrase is able to influence the topol. state of DNA mols. is of inherent interest from an enzymol. standpoint. In addn., much attention has been focused on DNA gyrase as the intracellular target of a no. of antibacterial agents and as a paradigm for other DNA topoisomerases.
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    Pietrusiński, M.; Staczek, P. Bacterial type II topoisomerases as targets for antibacterial drugs. Postepy Biochem. 2006, 52, 271– 282
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    Studies of structure and procaryotic functions of type II topoisomerases as an opportunity for development and synthesis of new antibacterial drugs
    Pietrusinski, Michal; Staczek, Pawel
    Postepy Biochemii (2006), 52 (3), 271-282CODEN: PSTBAH; ISSN:0032-5422. (Polskie Towarzystwo Biochemiczne)
    A review. Bacterial type II DNA topoisomerases are essential enzymes for correct genome functioning and cell growth. Gyrase is responsible for maintaining neg. supercoiling of bacterial chromosome, whereas topoisomerase IV acts in disentangling daughter chromosomes following replication. Type II DNA topoisomerases possess an ATP binding site, which can be treated as a target for antibacterial drugs. Resolving crystal structures of protein fragments consisting of an ATP binding site complexed with ADPNP/antibiotics have proven to be valuable for the understanding of the mode of action of existing antibacterial agents and presented new possibilities for novel drug design. Coumarins, quinolones and cyclothialidines are diverse group of antibiotics that interfere with type II DNA topoisomerases, however their mode of action is different. Recently a new class of antibiotics, simociclinones, was characterized. Their mechanism of action towards gyrase is entirely distinct from already known modes of action, therefore demonstrating the potential for development of novel anti-bacterial agents.
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    Bradbury, B. J.; Pucci, M. J. Recent Advances in Bacterial Topoisomerase Inhibitors. Curr. Opin. Pharmacol. 2008, 8, 574– 581,  DOI: 10.1016/j.coph.2008.04.009
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    Recent advances in bacterial topoisomerase inhibitors
    Bradbury, Barton J.; Pucci, Michael J.
    Current Opinion in Pharmacology (2008), 8 (5), 574-581CODEN: COPUBK; ISSN:1471-4892. (Elsevier B.V.)
    A review. Bacterial topoisomerase inhibitors continue to be actively developed as clin. antibacterial agents, largely owing to the success of the currently marketed inhibitors, the quinolones, and the increasing resistance to these agents. New quinolone analogs such as isothiazoloquinolones and quinazolinediones show some potential in overcoming this problem. Quinolones linked to other antibacterial agents such as rifamycins and oxazolidinones are designed to overcome both quinolone-specific resistance and resistance to the coupled agents. Novel inhibitors targeting non-quinolone-binding regions of topoisomerase continue to expand beyond the known coumarin class. The benzimidazoles and pyrazoles have shown promise but have been surpassed into the clinic by novel quinolines. Improved screening techniques and high-throughput methods offer new hope of further expanding the chem. space of topoisomerase inhibitors.
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    Ronkin, S. M.; Badia, M.; Bellon, S.; Grillot, A.-L.; Gross, C. H.; Grossman, T. H.; Mani, N.; Parsons, J. D.; Stamos, D.; Trudeau, M.; Wei, Y.; Charifson, P. S. Discovery of Pyrazolthiazoles as Novel and Potent Inhibitors of Bacterial Gyrase. Bioorg. Med. Chem. Lett. 2010, 20, 2828– 2831,  DOI: 10.1016/j.bmcl.2010.03.052
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    Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase
    Ronkin, Steven M.; Badia, Michael; Bellon, Steve; Grillot, Anne-Laure; Gross, Christian H.; Grossman, Trudy H.; Mani, Nagraj; Parsons, Jonathan D.; Stamos, Dean; Trudeau, Martin; Wei, Yunyi; Charifson, Paul S.
    Bioorganic & Medicinal Chemistry Letters (2010), 20 (9), 2828-2831CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compds. were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphlococcus aureus GyrB.
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    Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial—Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS Infect. Dis. 2015, 1, 4– 41,  DOI: 10.1021/id500013t
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    A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV
    Bisacchi, Gregory S.; Manchester, John I.
    ACS Infectious Diseases (2015), 1 (1), 4-41CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
    A review. The introduction into clin. practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clin. proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I. In this review, we analyze the historical attempts to discover and develop agents within this class and highlight factors that might have hindered those efforts. Within the last 15 years, however, our tech. understanding of the mol. details of the inhibition of the gyrase and topo IV ATPases, the factors governing resistance development to such inhibitors, and our knowledge of the phys. properties required for robust clin. drug candidates have all matured to the point wherein the industry may now address this mechanism of action with greater confidence. The antibacterial spectrum within this class has recently been extended to begin to include serious Gram neg. pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In spite of this recent tech. progress, adverse economics assocd. with antibacterial R&D over the last 20 years has diminished industry's ability to commit the resources and perseverance needed to bring new-class agents to launch. Consequently, a no. of recent efforts in the ATPase class have been derailed by organizational rather than scientific factors. Nevertheless, within this context we discuss the unique opportunity for the development of ATPase inhibitors of gyrase and topo IV as new-class antibacterial agents with broad spectrum potential.
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  21. 21
    Stokes, N. R.; Thomaides-Brears, H. B.; Barker, S.; Bennett, J. M.; Berry, J.; Collins, I.; Czaplewski, L. G.; Gamble, V.; Lancett, P.; Logan, A.; Lunniss, C. J.; Peasley, H.; Pommier, S.; Price, D.; Smee, C.; Haydon, D. J. Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases. Antimicrob. Agents Chemother. 2013, 57, 5977– 5986,  DOI: 10.1128/AAC.00719-13
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    Biological evaluation of benzothiazole ethyl urea inhibitors of bacterial type II topoisomerases
    Stokes Neil R; Thomaides-Brears Helena B; Barker Stephanie; Bennett James M; Berry Joanne; Collins Ian; Czaplewski Lloyd G; Gamble Vicki; Lancett Paul; Logan Alastair; Lunniss Christopher J; Peasley Hilary; Pommier Stephanie; Price Daniel; Smee Carol; Haydon David J
    Antimicrobial agents and chemotherapy (2013), 57 (12), 5977-86 ISSN:.
    The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.
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    O’Neill, A. J.; Chopra, I. Preclinical Evaluation of Novel Antibacterial Agents by Microbiological and Molecular Techniques. Expert Opin. Invest. Drugs 2004, 13, 1045– 1063,  DOI: 10.1517/13543784.13.8.1045
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    Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques
    O'Neill, Alex J.; Chopra, Ian
    Expert Opinion on Investigational Drugs (2004), 13 (8), 1045-1063CODEN: EOIDER; ISSN:1354-3784. (Ashley Publications Ltd.)
    A review. The defining property of an antibacterial agent is its ability to selectively interfere with bacterial growth and/or survival. Consequently, a considerable and crucial part of the preclin. evaluation of any novel antibacterial drug involves judging and characterizing its effects on bacteria in vitro. These crit. stages in drug development are sometimes made to appear somewhat trivial, sandwiched as they are between the highly demanding antibacterial discovery process and the formidable task of demonstrating safety and efficacy in vivo. However, careful biol. evaluation in vitro is key to quantifying and understanding the basis of the antibacterial activity, providing preliminary indications and evaluations of therapeutic potential, assessing the likelihood for the development of bacterial resistance, guiding chem. refinement and assisting subsequent stages of the appraisal of any new antibacterial drug. This review covers concepts in, and strategies for, the in vitro microbiol. and mol. evaluation of antibacterial drug candidates.
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  23. 23
    Axford, L. C.; Agarwal, P. K.; Anderson, K. H.; Andrau, L. N.; Atherall, J.; Barker, S.; Bennett, J. M.; Blair, M.; Collins, I.; Czaplewski, L. G.; Davies, D. T.; Gannon, C. T.; Kumar, D.; Lancett, P.; Logan, A.; Lunniss, C. J.; Mitchell, D. R.; Offermann, D. A.; Palmer, J. T.; Palmer, N.; Pitt, G. R.; Pommier, S.; Price, D.; Narasinga Rao, B.; Saxena, R.; Shukla, T.; Singh, A. K.; Singh, M.; Srivastava, A.; Steele, C.; Stokes, N. R.; Thomaides-Brears, H. B.; Tyndall, E. M.; Watson, D.; Haydon, D. J. Design, Synthesis and Biological Evaluation of α-Substituted Isonipecotic Acid Benzothiazole Analogues as Potent Bacterial Type II Topoisomerase Inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6598– 6603,  DOI: 10.1016/j.bmcl.2013.10.058
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    23
    Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors
    Axford, Lorraine C.; Agarwal, Piyush K.; Anderson, Kelly H.; Andrau, Laura N.; Atherall, John; Barker, Stephanie; Bennett, James M.; Blair, Michael; Collins, Ian; Czaplewski, Lloyd G.; Davies, David T.; Gannon, Carlie T.; Kumar, Dushyant; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J.; Mitchell, Dale R.; Offermann, Daniel A.; Palmer, James T.; Palmer, Nicholas; Pitt, Gary R. W.; Pommier, Stephanie; Price, Daniel; Narasinga Rao, B.; Saxena, Rashmi; Shukla, Tarun; Singh, Amit K.; Singh, Mahipal; Srivastava, Anil; Steele, Christopher; Stokes, Neil R.; Thomaides-Brears, Helena B.; Tyndall, Edward M.; Watson, David; Haydon, David J.
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (24), 6598-6603CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The discovery and optimization of a new class of benzothiazole small mols. (e.g. I) that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogs bearing an α-substituent to the carboxylic acid group, resulting in excellent soly. and favorable pharmacokinetic properties.
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    Barančoková, M.; Kikelj, D.; Ilaš, J. Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors. Future Med. Chem. 2018, 10, 1207– 1227,  DOI: 10.4155/fmc-2017-0257
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    Recent progress in the discovery and development of DNA gyrase B inhibitors
    Barancokova, Michaela; Kikelj, Danijel; Ilas, Janez
    Future Medicinal Chemistry (2018), 10 (10), 1207-1227CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    A review. New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topol. during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular ref. to Gram-neg. bacteria. Graphical abstr. :.
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    Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-Based Discovery of Substituted 4,5′-Bithiazoles as Novel DNA Gyrase Inhibitors. J. Med. Chem. 2012, 55, 6413– 6426,  DOI: 10.1021/jm300395d
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    Structure-Based Discovery of Substituted 4,5'-Bithiazoles as Novel DNA Gyrase Inhibitors
    Brvar, Matjaz; Perdih, Andrej; Renko, Miha; Anderluh, Gregor; Turk, Dusan; Solmajer, Tom
    Journal of Medicinal Chemistry (2012), 55 (14), 6413-6426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N2-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallog., confirming our initial in silico binding model. Furthermore, the high resoln. of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
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    Liu, J.; Li, X.-W.; Guo, Y.-W. Recent Advances in the Isolation, Synthesis and Biological Activity of Marine Guanidine Alkaloids. Mar. Drugs 2017, 15, 324,  DOI: 10.3390/md15100324
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    Recent advances in the isolation, synthesis and biological activity of marine guanidine alkaloids
    Liu, Jin; Li, Xu-Wen; Guo, Yue-Wei
    Marine Drugs (2017), 15 (10), 324/1-324/19CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    Marine organisms are prolific resources of guanidine-contg. natural products with intriguing structures and promising biol. activities. These mols. have therefore attracted the attention of chemists and biologists for their further studies towards potential drug leads. This review focused on the guanidine alkaloids derived from marine sources and discussed the recent progress on their isolation, synthesis and biol. activities, covering the literature from the year 2010 to the present.
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    Netz, N.; Opatz, T. Marine Indole Alkaloids. Mar. Drugs 2015, 13, 4814– 4914,  DOI: 10.3390/md13084814
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    Marine indole alkaloids
    Netz, Natalie; Opatz, Till
    Marine Drugs (2015), 13 (8), 4814-4914CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    Marine indole alkaloids comprise a large and steadily growing group of secondary metabolites. Their diverse biol. activities make many compds. of this class attractive starting points for pharmaceutical development. Several marine-derived indoles were found to possess cytotoxic, antineoplastic, antibacterial and antimicrobial activities, in addn. to the action on human enzymes and receptors. The newly isolated indole alkaloids of marine origin since the last comprehensive review in 2003 are reported, and biol. aspects will be discussed.
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  28. 28
    Parrino, B.; Attanzio, A.; Spanò, V.; Cascioferro, S.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Diana, P.; Cirrincione, G.; Carbone, A. Synthesis, Antitumor Activity and CDK1 Inhibiton of New Thiazole Nortopsentin Analogues. Eur. J. Med. Chem. 2017, 138, 371– 383,  DOI: 10.1016/j.ejmech.2017.06.052
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    Synthesis, antitumor activity and CDK1 inhibition of new thiazole nortopsentin analogues
    Parrino, Barbara; Attanzio, Alessandro; Spano, Virginia; Cascioferro, Stella; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Diana, Patrizia; Cirrincione, Girolamo; Carbone, Anna
    European Journal of Medicinal Chemistry (2017), 138 (), 371-383CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A new series of thiazole nortopsentin analogs was conveniently synthesized with fair overall yields. The antiproliferative activity of the new derivs. was tested against different human tumor cell lines of the NCI full panel. Four of them, e. g., I, showed good antitumor activity with GI50 values from micro to nanomolar level. The mechanism of the antiproliferative effect of these derivs., was pro-apoptotic, being assocd. with externalization of plasma membrane phosphatidylserine and DNA fragmentation. The most active and selective of the new thiazoles confined viable cells in G2/M phase and markedly inhibited in vitro CDK1 activity.
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    Parrino, B.; Schillaci, D.; Carnevale, I.; Giovannetti, E.; Diana, P.; Cirrincione, G.; Cascioferro, S. Synthetic Small Molecules as Anti-Biofilm Agents in the Struggle against Antibiotic Resistance. Eur. J. Med. Chem. 2019, 161, 154– 178,  DOI: 10.1016/j.ejmech.2018.10.036
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    Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance
    Parrino, Barbara; Schillaci, Domenico; Carnevale, Ilaria; Giovannetti, Elisa; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
    European Journal of Medicinal Chemistry (2019), 161 (), 154-178CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. Biofilm formation significantly contributes to microbial survival in hostile environments and it is currently considered a key virulence factor for pathogens responsible for serious chronic infections. In the last decade many efforts have been made to identify new agents able to modulate bacterial biofilm life cycle, and many compds. have shown interesting activities in inhibiting biofilm formation or in dispersing pre-formed biofilms. However, only a few of these compds. were tested using in vivo models for their clin. significance. Contrary to conventional antibiotics, most of the anti-biofilm compds. act as anti-virulence agents as they do not affect bacterial growth. In this review we selected the most relevant literature of the last decade, focusing on the development of synthetic small mols. able to prevent bacterial biofilm formation or to eradicate pre-existing biofilms of clin. relevant Gram-pos. and Gram-neg. pathogens. In addn., we provide a comprehensive list of the possible targets to counteract biofilm formation and development, as well as a detailed discussion the advantages and disadvantages of the different current biofilm-targeting strategies.
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    Ballard, T. E.; Richards, J. J.; Aquino, A.; Reed, C. S.; Melander, C. Antibiofilm activiy of a diverse oroidin library, generated through reductive acylation. J. Org. Chem. 2009, 74, 1755– 1758,  DOI: 10.1021/jo802260t
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    Antibiofilm Activity of a Diverse Oroidin Library Generated through Reductive Acylation
    Ballard, T. Eric; Richards, Justin J.; Aquino, Arianexys; Reed, Catherine S.; Melander, Christian
    Journal of Organic Chemistry (2009), 74 (4), 1755-1758CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    A diverse 20-compd. library of analogs, e.g. I, based on the marine alkaloid oroidin were synthesized via a reductive acylation strategy. The final target was then assayed for inhibition and dispersion activity against common proteobacteria known to form biofilms. This methodol. represents a significant improvement over the generality of known methods to acylate substrates contg. 2-aminoimidazoles and has the potential to have broad application to the synthesis of more advanced oroidin family members and their corresponding analogs.
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    Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, C. Synthesis and Screening of an Oroidin Library against Pseudomonas Aeruginosa Biofilms. ChemBioChem 2008, 9, 1267– 1279,  DOI: 10.1002/cbic.200700774
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    Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms
    Richards, Justin J.; Ballard, T. Eric; Huigens, Robert W., III; Melander, Christian
    ChemBioChem (2008), 9 (8), 1267-1279CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A 50-compd. library based on the marine natural product oroidin was synthesized and assayed for anti-biofilm activity against PAO1 and PA14, two strains of the medically relevant γ-proteobacterium Pseudomonas aeruginosa. Through structure-activity relationship (SAR) anal. of analogs based on the oroidin template, several conclusion can be drawn as to what structural properties of the synthetic derivs. are necessary to elicit a biol. response. Notably, the most active analogs identified were those that contained a 2-aminoimidazole (2-Al) motif and a dibrominated pyrrolecarboxamide subunit. Here we disclose the synthesis and subsequently detd. biol. activity of this unique class of compds. as inhibitors of biofilm formation that have no direct antibiotic effect.
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    Hodnik, Ž.; Łoś, J. M.; Žula, A.; Zidar, N.; Jakopin, Ž.; Łoś, M.; Sollner Dolenc, M.; Ilaš, J.; Wȩgrzyn, G.; Peterlin Mašič, L.; Kikelj, D. Inhibition of Biofilm Formation by Conformationally Constrained Indole-Based Analogues of the Marine Alkaloid Oroidin. Bioorg. Med. Chem. Lett. 2014, 24, 2530– 2534,  DOI: 10.1016/j.bmcl.2014.03.094
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    Inhibition of biofilm formation by conformationally constrained indole-based analogs of the marine alkaloid oroidin
    Hodnik, Ziga; Los, Joanna M.; Zula, Ales; Zidar, Nace; Jakopin, Ziga; Los, Marcin; Sollner Dolenc, Marija; Ilas, Janez; Wegrzyn, Grzegorz; Peterlin Masic, Lucija; Kikelj, Danijel
    Bioorganic & Medicinal Chemistry Letters (2014), 24 (11), 2530-2534CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The authors describe indole-based analogs of oroidin as a novel class of 2-aminoimidazole-based inhibitors of methicillin-resistant Staphylococcus aureus biofilm formation and of 2-aminoimidazole-based inhibitors of Streptococcus mutans biofilm formation. This study highlighted the indole moiety as a dibromopyrrole mimetic for obtaining inhibitors of S. aureus and S. mutans biofilm formation. The most potent compd. in the series, 5-(trifluoromethoxy)indole-based analog 4b (MBIC50 = 20 μM), emerged as a promising hit for further optimization of novel inhibitors of S. aureus and S. mutans biofilms.
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    Tomašič, T.; Katsamakas, S.; Hodnik, Ž.; Ilaš, J.; Brvar, M.; Solmajer, T.; Montalvão, S.; Tammela, P.; Banjanac, M.; Ergović, G.; Anderluh, M.; Peterlin Mašič, L.; Kikelj, D. Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]Thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site. J. Med. Chem. 2015, 58, 5501– 5521,  DOI: 10.1021/acs.jmedchem.5b00489
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    Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site
    Tomasic, Tihomir; Katsamakas, Sotirios; Hodnik, Ziga; Ilas, Janez; Brvar, Matjaz; Solmajer, Tom; Montalvao, Sofia; Tammela, Paivi; Banjanac, Mihailo; Ergovic, Gabrijela; Anderluh, Marko; Masic, Lucija Peterlin; Kikelj, Danijel
    Journal of Medicinal Chemistry (2015), 58 (14), 5501-5521CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topol. state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogs, the authors identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologs. Some of the compds. possessed modest antibacterial activity against Gram pos. bacterial strains, while their evaluation against wild-type, impA and ΔtolCE. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochem. properties necessary for cell wall penetration. The study provides a rationale for optimization of this class of compds. toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
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    Gjorgjieva, M.; Tomašič, T.; Barančokova, M.; Katsamakas, S.; Ilaš, J.; Tammela, P.; Peterlin Mašič, L.; Kikelj, D. Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors. J. Med. Chem. 2016, 59, 8941– 8954,  DOI: 10.1021/acs.jmedchem.6b00864
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    Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors
    Gjorgjieva, Marina; Tomasic, Tihomir; Barancokova, Michaela; Katsamakas, Sotirios; Ilas, Janez; Tammela, Paivi; Peterlin Masic, Lucija; Kikelj, Danijel
    Journal of Medicinal Chemistry (2016), 59 (19), 8941-8954CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Bacterial DNA gyrase and topoisomerase IV control the topol. state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compd. 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV both from E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24, I) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compds. possessed weak antibacterial activity against Gram-pos. bacteria. These results provide a basis for structure-based optimization towards dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
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    Tomašič, T.; Mirt, M.; Barančoková, M.; Ilaš, J.; Zidar, N.; Tammela, P.; Kikelj, D. Design, Synthesis and Biological Evaluation of 4,5-Dibromo-N-(Thiazol-2-yl)-1H-Pyrrole-2-Carboxamide Derivatives as Novel DNA Gyrase Inhibitors. Bioorg. Med. Chem. 2017, 25, 338– 349,  DOI: 10.1016/j.bmc.2016.10.038
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    Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors
    Tomasic, Tihomir; Mirt, Matic; Barancokova, Michaela; Ilas, Janez; Zidar, Nace; Tammela, Paivi; Kikelj, Danijel
    Bioorganic & Medicinal Chemistry (2017), 25 (1), 338-349CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety was designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole-2,6-diamine derivs. inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 μM). Their "ring-opened" analogs, based on the 2-(2-aminothiazol-4-yl)acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 μM. Mol. docking expts. were conducted to study the binding modes of inhibitors.
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    Haroun, M.; Tratrat, C.; Kositzi, K.; Tsolaki, E.; Petrou, A.; Aldhubiab, B.; Attimarad, M.; Harsha, S.; Geronikaki, A.; Venugopala, K. N.; Elsewedy, H. S.; Sokovic, M.; Glamoclija, J.; Ciric, A. New Benzothiazole-Based Thiazolidinones as Potent Antimicrobial Agents. Design, Synthesis and Biological Evaluation. Curr. Top. Med. Chem. 2018, 18, 75– 87,  DOI: 10.2174/1568026618666180206101814
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    New Benzothiazole-based Thiazolidinones as Potent Antimicrobial Agents. Design, synthesis and Biological Evaluation
    Haroun, Michelyne; Tratrat, Christophe; Kositzi, Katerina; Tsolaki, Evangelia; Petrou, Anthi; Aldhubiab, Bandar; Attimarad, Mahesh; Harsha, Sree; Geronikaki, Athina; Venugopala, Katharigatta N.; Elsewedy, Heba S.; Sokovic, Marina; Glamoclija, Jasna; Ciric, Ana
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2018), 18 (1), 75-87CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    Thiazole and benzothiazole derivs., as well as thiazolidinones are very important scaffolds in medicinal chem. Literature has revealed that they possess a wide spectrum of biol. activities including antimicrobial activity. The goal of this paper is the designing of new benzothiazole based thiazolidinones and the evaluation of their biol. activities. The designed compds. were synthesized using classical org. synthesis methods. The antimicrobial activity was evaluated using the method of microdilution. The twelve newly synthesized compds. showed antimicrobial properties. All compds. appeared to be more active than ampicillin in most studied strains and in some cases, more active than streptomycin. Antifungal activity, in most cases was also better than the ref. drugs ketoconazole and bifonazole. The prediction of cytotoxicity revealed that the synthesized compds. were not toxic (LD50 350-1000 mg/kg of body wt.). Docking studies on the antibacterial activity confirmed the biol. results. The twelve new compds. were synthesized and studied for their antimicrobial activity. The compds. appeared to be promising antimicrobial agents and could be the lead compds. for new, more potent drugs. According to the docking prediction, the compds. could be MurB inhibitors.
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  37. 37
    Maddili, S. K.; Li, Z.-Z.; Kannekanti, V. K.; Bheemanaboina, R. R. Y.; Tuniki, B.; Tangadanchu, V. K. R.; Zhou, C.-H. Azoalkyl Ether Imidazo[2,1-b]Benzothiazoles as Potentially Antimicrobial Agents with Novel Structural Skeleton. Bioorg. Med. Chem. Lett. 2018, 28, 2426– 2431,  DOI: 10.1016/j.bmcl.2018.06.016
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    Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton
    Maddili, Swetha Kameswari; Li, Zhen-Zhen; Kannekanti, Vijaya Kumar; Bheemanaboina, Rammohan R. Yadav; Tuniki, Balaraju; Tangadanchu, Vijai Kumar Reddy; Zhou, Cheng-He
    Bioorganic & Medicinal Chemistry Letters (2018), 28 (14), 2426-2431CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good no. of the prepd. derivs. exhibited significant inhibitory properties against most of the tested strains. Esp. 2-methyl-5-nitroimidazole deriv. I presented superior inhibitory activity against MRSA and B. typhi with MIC = 4 μg/mL and MIC = 1 μg/mL, resp. The highly active compd. I showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. A mol. docking study exposed that the active mol. I could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chem. studies were also performed to explain the high antibacterial activity. Further investigation revealed that compd. I could significantly assoc. with gyrase-DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form I-DNA supramol. complex, which impart potent bioactivity.
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    Hameed, A.; Al-Rashida, M.; Uroos, M.; Abid Ali, S.; Khan, K. M. Schiff bases in medicinal chemistry: a patent review (2010–2015). Expert Opin. Ther. Pat. 2017, 27, 63– 79,  DOI: 10.1080/13543776.2017.1252752
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    Schiff bases in medicinal chemistry: a patent review (2010-2015)
    Hameed, Abdul; al-Rashida, Mariya; Uroos, Maliha; Ali, Syed Abid; Khan, Khalid Mohammed
    Expert Opinion on Therapeutic Patents (2017), 27 (1), 63-79CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
    A review. Schiff bases are synthetically accessible and structurally diverse compds., typically obtained by facile condensation between an aldehyde, or a ketone with primary amines. Schiff bases contain an azomethine (-C = N-) linkage that stitches together two or more biol. active arom./heterocyclic scaffolds to form various mol. hybrids with interesting biol. properties. Schiff bases are versatile metal complexing agents and have been known to coordinate all metals to form stable metal complexes with vast therapeutic applications. This review aims to provide a comprehensive overview of the various patented therapeutic applications of Schiff bases and their metal complexes from 2010 to 2015. Schiff bases are a popular class of compds. with interesting biol. properties. Schiff bases are also versatile metal complexing ligands and have been used to coordinate almost all d-block metals as well as lanthanides. Therapeutically, Schiff bases and their metal complexes have been reported to exhibit a wide range of biol. activities such as antibacterial including antimycobacterial, antifungal, antiviral, antimalarial, antiinflammatory, antioxidant, pesticidal, cytotoxic, enzyme inhibitory, and anticancer including DNA damage.
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    Nastasǎ, C.; Vodnar, D. C.; Ionuţ, I.; Stana, A.; Benedec, D.; Tamaian, R.; Oniga, O.; Tiperciuc, B. Antibacterial Evaluation and Virtual Screening of New Thiazolyl-Triazole Schiff Bases as Potential DNA-Gyrase Inhibitors. Int. J. Mol. Sci. 2018, 19, 222  DOI: 10.3390/ijms19010222
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    Antibacterial evaluation and virtual screening of new thiazolyl-triazole schiff bases as potential DNA-gyrase inhibitors
    Nastasa, Cristina; Vodnar, Dan C.; Ionut, Ioana; Anca Stana; Daniela Benedec; Tamaian, Radu; Oniga, Ovidiu; Tiperciuc, Brindusa
    International Journal of Molecular Sciences (2018), 19 (1), 222/1-222/18CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    The global spread of bacterial resistance to drugs used in therapy requires new potent and safe antimicrobial agents. DNA gyrases represent important targets in drug discovery. Schiff bases, thiazole, and triazole derivs. are considered key scaffolds in medicinal chem. Fifteen thiazolyl-triazole Schiff bases were evaluated for their antibacterial activity, measuring the growth inhibition zone diam., the min. inhibitory concn. (MIC), and the min. bactericidal concn. (MBC), against Gram-pos. (Staphylococcus aureus, Listeria monocytogenes) and Gram-neg. (Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa) bacteria. The inhibition of S. aureus and S. typhimurium was modest. Compds. B1, B2, and B9 showed a similar effect as ciprofloxacin, the antimicrobial ref., against L. monocytogenes. B10 displayed a better effect. Derivs. B1, B5#x2013;7, B9, and B11-15 expressed MIC values lower than the ref., against L. monocytogenes. B5, B6, and B11-15 strongly inhibited the growth of P. aeruginosa. All compds. were subjected to an in silico screening of the ADMET (absorption, distribution, metab., elimination, toxicity) properties. Mol. docking was performed on the gyrA and gyrB from L. monocytogenes. The virtual screening concluded that thiazolyl-triazole Schiff base B8 is the best drug-like candidate, satisfying requirements for both safety and efficacy, being more potent against the bacterial gyrA than ciprofloxacin.
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    Eakin, A. E.; Green, O.; Hales, N.; Walkup, G. K.; Bist, S.; Singh, A.; Mullen, G.; Bryant, J.; Embrey, K.; Gao, N.; Breeze, A.; Timms, D.; Andrews, B.; Uria-Nickelsen, M.; Demeritt, J.; Loch, J. T., 3rd; Hull, K.; Blodgett, A.; Illingworth, R. N.; Prince, B.; Boriack-Sjodin, P. A.; Hauck, S.; MacPherson, L. J.; Ni, H.; Sherer, B. Pyrrolamide DNA Gyrase Inhibitors: Fragment-Based Nuclear Magnetic Resonance Screening to Identify Antibacterial Agents. Antimicrob. Agents Chemother. 2012, 56, 1240– 1246,  DOI: 10.1128/AAC.05485-11
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    Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents
    Eakin, Ann E.; Green, Oluyinka; Hales, Neil; Walkup, Grant K.; Bist, Shanta; Singh, Alok; Mullen, George; Bryant, Joanna; Embrey, Kevin; Gao, Ning; Breeze, Alex; Timms, Dave; Andrews, Beth; Uria-Nickelsen, Maria; Demeritt, Julie; Loch, James T., III; Hull, Ken; Blodgett, April; Illingworth, Ruth N.; Prince, Bryan; Boriack-Sjodin, P. Ann; Hauck, Sheila; MacPherson, Lawrence J.; Ni, Haihong; Sherer, Brian
    Antimicrobial Agents and Chemotherapy (2012), 56 (3), 1240-1246CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compds. were identified by a fragment-based lead generation (FBLG) approach using NMR (NMR) screening to identify low-mol.-wt. compds. that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding const. of 1 mM formed the basis of the design and synthesis of a focused library of compds. that resulted in the rapid identification of a lead compd. that inhibited DNA gyrase with a 50% inhibitory concn. (IC50) of 3 μM. The potency of the lead compd. was further optimized by utilizing iterative X-ray crystallog. to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates contg. pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compds. was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clin. indications.
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    Sherer, B. A.; Hull, K.; Green, O.; Basarab, G.; Hauck, S.; Hill, P.; Loch, J. T.; Mullen, G.; Bist, S.; Bryant, J.; Boriack-Sjodin, A.; Read, J.; DeGrace, N.; Uria-Nickelsen, M.; Illingworth, R. N.; Eakin, A. E. Pyrrolamide DNA Gyrase Inhibitors: Optimization of Antibacterial Activity and Efficacy. Bioorg. Med. Chem. Lett. 2011, 21, 7416– 7420,  DOI: 10.1016/j.bmcl.2011.10.010
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    Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy
    Sherer, Brian A.; Hull, Kenneth; Green, Oluyinka; Basarab, Gregory; Hauck, Sheila; Hill, Pamela; Loch, James T., III; Mullen, George; Bist, Shanta; Bryant, Joanna; Boriack-Sjodin, Ann; Read, Jon; DeGrace, Nancy; Uria-Nickelsen, Maria; Illingworth, Ruth N.; Eakin, Ann E.
    Bioorganic & Medicinal Chemistry Letters (2011), 21 (24), 7416-7420CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochem. activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the mol. resulted in pyrrolamides with improved cellular activity and in vivo efficacy.
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    Basarab, G. S.; Hill, P. J.; Garner, C. E.; Hull, K.; Green, O.; Sherer, B. A.; Dangel, P. B.; Manchester, J. I.; Bist, S.; Hauck, S.; Zhou, F.; Uria-Nickelsen, M.; Illingworth, R. N.; Alm, R.; Rooney, M.; Eakin, A. E. Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099). J. Med. Chem. 2014, 57, 6060– 6082,  DOI: 10.1021/jm500462x
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    Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)
    Basarab, Gregory S.; Hill, Pamela J.; Garner, C. Edwin; Hull, Ken; Green, Oluyinka; Sherer, Brian A.; Dangel, P. Brian; Manchester, John I.; Bist, Shanta; Hauck, Sheila; Zhou, Fei; Uria-Nickelsen, Maria; Illingworth, Ruth; Alm, Richard; Rooney, Mike; Eakin, Ann E.
    Journal of Medicinal Chemistry (2014), 57 (14), 6060-6082CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    AZD5099 I is an antibacterial agent that entered phase 1 clin. trials targeting infections caused by Gram-pos. and fastidious Gram-neg. bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramol. hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compd. I showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency vs. the drug was low, and reports of clin. resistance due to alteration of the target are few. Hence, I could offer a novel treatment for serious issues of resistance to currently used antibacterials.
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    Yang, Y.; Severin, A.; Chopra, R.; Krishnamurthy, G.; Singh, G.; Hu, W.; Keeney, D.; Svenson, K.; Petersen, P. J.; Labthavikul, P.; Shlaes, D. M.; Rasmussen, B. A.; Failli, A. A.; Shumsky, J. S.; Kutterer, K. M.; Gilbert, A.; Mansour, T. S. 3,5-Dioxopyrazolidines, Novel Inhibitors of UDP-N- Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria. Antimicrob. Agents Chemother. 2006, 50, 556– 564,  DOI: 10.1128/AAC.50.2.556-564.2006
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    3,5-Dioxopyrazolidines, novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB) with activity against Gram-positive bacteria
    Yang, Youjun; Severin, Anatoly; Chopra, Rajiv; Krishnamurthy, Girija; Singh, Guy; Hu, William; Keeney, David; Svenson, Kristine; Petersen, Peter J.; Labthavikul, Pornpen; Shlaes, David M.; Rasmussen, Beth A.; Failli, Amedeo A.; Shumsky, Jay S.; Kutterer, Kristina M. K.; Gilbert, Adam; Mansour, Tarek S.
    Antimicrobial Agents and Chemotherapy (2006), 50 (2), 556-564CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compds. I, II, and III, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphylococcus aureus MurB, and E. coli MurA with 50% inhibitory concns. (IC50s) in the range of 4.1-6.8 μM, 4.3-10.3 μM, and 6.8-29.4 μM, resp. Compd. IV, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC50s, 24.5-35 μM). A fluorescence-binding assay indicated tight binding of III with E. coli MurB, giving a dissocn. const. of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with IV was obtained at 2.4 Å resoln. The crystal structure indicated the binding of a compd. at the active site of MurB and specific interactions with active-site residues and the bound FAD cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC50s of 0.39-11.1 μM. Antibacterial activity was obsd. for I-III (MICs, 0.25-16 μg/mL) and IV (MICs, 4-8 μg/mL) against gram-pos. bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
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    Bronson, J. J.; DenBleyker, K. L.; Falk, P. J.; Mate, R. A.; Ho, H.-T.; Pucci, M. J.; Snyder, L. B. Discovery of the First Antibacterial Small Molecule Inhibitors of MurB. Bioorg. Med. Chem. Lett. 2003, 13, 873– 875,  DOI: 10.1016/S0960-894X(02)01076-4
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    Discovery of the first antibacterial small molecule inhibitors of MurB
    Bronson, Joanne J.; DenBleyker, Kenneth L.; Falk, Paul J.; Mate, Robert A.; Ho, Hsu-Tso; Pucci, Michael J.; Snyder, Lawrence B.
    Bioorganic & Medicinal Chemistry Letters (2003), 13 (5), 873-875CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
    A series of imidazolinone analogs was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity. Analogs of a known MurB enzyme inhibitor, 5-[2-[[2-(2-chlorophenyl)ethyl]amino]-2-oxoethyl]-α-butyl-2-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-4-oxo-(αS)-3-thiazolidineacetic acid, were prepd. and evaluated as antibacterial agents. Analogs included derivs. of α-butyl-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid Me ester and α-butyl-3-[2-[[2-(2-chlorophenyl)ethyl]amino]-2-oxoethyl]-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid and α-butyl-3-[2-[[(3,4-dichlorophenyl)methyl]amino]-2-oxoethyl]-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid. MurB has no known counterpart in eukaryotes.
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    Liaras, K.; Fesatidou, M.; Geronikaki, A. Thiazoles and Thiazolidinones as COX/LOX Inhibitors. Molecules 2018, 23, 685,  DOI: 10.3390/molecules23030685
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    Thiazoles and thiazolidinones as COX/LOX inhibitors
    Liaras, Konstantinos; Fesatidou, Maria; Geronikaki, Athina
    Molecules (2018), 23 (3), 685/1-685/21CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the prodn. of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a no. of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biol. active compds. of natural origin, as well as synthetic mols. that possess a wide range of pharmacol. activities. This review focuses on the biol. activity of several thiazole and thiazolidinone derivs. as COX-1/COX-2 and LOX inhibitors.
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    Pattan, S. R.; Kekare, P.; Patil, A.; Nikalje, A.; Kittur, B. S. Studies on the Synthesis of Novel 2,4-Thiazolidinedione Derivatives with Antidiabetic Activity. Iran. J. Pharm. Sci. 2009, 5, 225– 230
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    Studies on the synthesis of novel 2,4-thiazolidinedione derivatives with antidiabetic activity
    Pattan, Shashikant R.; Kekare, Prajact; Patil, Ashwini; Nikalje, Ana; Kittur, B. S.
    Iranian Journal of Pharmaceutical Sciences (2009), 5 (4), 225-230CODEN: IJPSUU; ISSN:1735-2444. (Shiraz University of Medical Sciences, Faculty of Pharmacy)
    A new series of thiazolidinediones was synthesized. The structures of these compds. were established by IR, 1H NMR, and elemental anal. All of the compds. were screened for antidiabetic activity on albino rats. Most of the compds. showed significant antidiabetic activity when compared with the std. glibenclamide.
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    Suryawanshi, R.; Jadhav, S.; Makwana, N.; Desai, D.; Chaturbhuj, D.; Sonawani, A.; Idicula-Thomas, S.; Murugesan, V.; Katti, S. B.; Tripathy, S.; Paranjape, R.; Kulkarni, S. Evaluation of 4-Thiazolidinone Derivatives as Potential Reverse Transcriptase Inhibitors against HIV-1 Drug Resistant Strains. Bioorg. Chem. 2017, 71, 211– 218,  DOI: 10.1016/j.bioorg.2017.02.007
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    Evaluation of 4-thiazolidinone derivatives as potential reverse transcriptase inhibitors against HIV-1 drug resistant strains
    Suryawanshi, Rahul; Jadhav, Sushama; Makwana, Nandini; Desai, Dipen; Chaturbhuj, Devidas; Sonawani, Archana; Idicula-Thomas, Susan; Murugesan, Vanangamudi; Katti, Seturam B.; Tripathy, Srikanth; Paranjape, Ramesh; Kulkarni, Smita
    Bioorganic Chemistry (2017), 71 (), 211-218CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
    Rapid emergence of drug resistance is crucial in management of HIV infection limiting implementation of efficacious drugs in the ART regimen. Designing new mols. against HIV drug resistant strains is utmost essential. Based on the anti-HIV-1 activity, we selected four 4-thiazolidinone derivs. (S009-1908, S009-1909, S009-1911, S009-1912) and studied their interaction with reverse transcriptase (RT) from a panel of 10 clin. isolates (8 nevirapine resistant and two susceptible) using in silico methods, and inhibition pattern using in vitro cell based assays. On the basis of binding affinity obsd. in in silico anal., 2-(2-chloro-6-nitrophenyl)-3-(4, 6-dimethylpyridin-2-yl) thiazolidin-4-one (S009-1912) was identified as the lead mol. followed by S009-1908, S009-1909 and S009-1911. The in vitro activity against the same panel was assessed using TZM-bl assay (IC50: 0.4-11.44 μg/mL, TI: 4-126) and subsequently in PBMC assay against a nevirapine resistant clin. isolate (IC50: 0.8-6.65 μg/mL, TI: 8.31-11.43) and std. strain from NIH ARRRP (IC50: 0.95-3.6 μg/mL, TI: 9-26). The study shows analog with pyrimidin-2-yl amino substitution at N-3 position of thiazolidin-4-one ring (S009-1908, S009-1909, S009-1911) exhibited enhanced activity as compared to pyridin-2-yl substituted derivs. (S009-1912), suggesting the use 4-thiazolidinones for developing potent inhibitors against HIV-1 drug resistant strains.
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    Kesicki, E. A.; Bailey, M. A.; Ovechkina, Y.; Early, J. V.; Alling, T.; Bowman, J.; Zuniga, E. S.; Dalai, S.; Kumar, N.; Masquelin, T.; Hipskind, P. A.; Odingo, J. O.; Parish, T. Synthesis and Evaluation of the 2-Aminothiazoles as Anti-Tubercular Agents. PLoS One 2016, 11, e0155209  DOI: 10.1371/journal.pone.0155209
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    Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
    Kesicki, Edward A.; Bailey, Mai A.; Ovechkina, Yulia; Early, Julie V.; Alling, Torey; Bowman, Julie; Zuniga, Edison S.; Dalai, Suryakanta; Kumar, Naresh; Masquelin, Thierry; Hipskind, Philip A.; Odingo, Joshua O.; Parish, Tanya
    PLoS One (2016), 11 (5), e0155209/1-e0155209/25CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large no. of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We detd. that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar min. inhibitory concns. being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel antitubercular agents.
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  49. 49
    Marques, G. H.; Kunzler, A.; Bareño, V. D. O.; Drawanz, B. B.; Mastelloto, H. G.; Leite, F. R. M.; Nascimento, G. G.; Nascente, P. S.; Siqueira, G. M.; Cunico, W. Antifungal Activity of 3-(Heteroaryl-2-yl-methyl)Thiazolidinone Derivatives. Med. Chem. 2014, 10, 355– 360,  DOI: 10.2174/15734064113099990030
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    Antifungal Activity of 3-(heteroaryl-2-ylmethyl)thiazolidinone Derivatives
    Marques, Gabriela H.; Kunzler, Alice; Bareno, Valeria D. O.; Drawanz, Bruna B.; Mastelloto, Hellen G.; Leite, Fabio R. M.; Nascimento, Gustavo G.; Nascente, Patricia S.; Siqueira, Geonir M.; Cunico, Wilson
    Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 10 (4), 355-360CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
    Thiazolidinones, synthesized from multicomponent reactions of 2-heteroarylmethylamine, arenealdehydes and mercaptoacetic acid, have been tested against six yeasts, namely Candida albicans, C. parapsilosis, C. guilliermondii, Cryptococcus laurentii, Trichosporon asahii and Rhodotorula spp. The activities were expressed as min. inhibitory concns. (MIC) and the min. fungicidal concns. (MFC). The most affected yeasts were Rhodotorula spp. and T. asahii. The cytotoxicities of the thiazolidinones against the fibroblast 3T3/NIH cell line are also described. The antifungal results and the low cytotoxicity of the compds. in this work provide good guides for the further development of active compds.
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    Gupta, A.; Singh, R.; Sonar, P. K.; Saraf, S. K. Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation. Biochem. Res. Int. 2016, 2016 (216), 8086762,  DOI: 10.1155/2016/8086762
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    Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation
    Gupta Amit; Singh Rajendra; Sonar Pankaj K; Saraf Shailendra K
    Biochemistry research international (2016), 2016 (), 8086762 ISSN:2090-2247.
    A series of new 4-thiazolidinone derivatives was synthesized, characterized by spectral techniques, and screened for antimicrobial activity. All the compounds were evaluated against five Gram-positive bacteria, two Gram-negative bacteria, and two fungi, at concentrations of 50, 100, 200, 400, 800, and 1600 μg/mL, respectively. Minimum inhibitory concentrations of all the compounds were also determined and were found to be in the range of 100-400 μg/mL. All the compounds showed moderate-to-good antimicrobial activity. Compounds 4a [2-(4-fluoro-phenyl)-3-(4-methyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-thiazolidin-4-one] and 4e [3-(4,6-dimethyl-pyrimidin-2-yl)-2-(2-methoxy-phenyl)-thiazolidin-4-one] were the most potent compounds of the series, exhibiting marked antimicrobial activity against Pseudomonas fluorescens, Staphylococcus aureus, and the fungal strains. Thus, on the basis of results obtained, it may be concluded that synthesized compounds exhibit a broad spectrum of antimicrobial activity.
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    Andres, C. J.; Bronson, J. J.; D’Andrea, S. V.; Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.; Harte, W. E.; Ho, H.-T.; Misco, P. F.; Robertson, J. G.; Stock, D.; Sun, Y.; Walsh, A. W. 4-Thiazolidinones: Novel Inhibitors of the Bacterial Enzyme MurB. Bioorg. Med. Chem. Lett. 2000, 10, 715– 717,  DOI: 10.1016/S0960-894X(00)00073-1
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    4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB
    Andres, Charles J.; Bronson, Joanne J.; D'Andrea, Stanley V.; Deshpande, Milind S.; Falk, Paul J.; Grant-Young, Katharine A.; Harte, William E.; Ho, Hsu-Tso; Misco, Peter F.; Robertson, James G.; Stock, David; Sun, Yaxiong; Walsh, Ann W.
    Bioorganic & Medicinal Chemistry Letters (2000), 10 (8), 715-717CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
    4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the enzyme in vitro. This activity, coupled with the design principles of the thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biol. selector.
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    Patel, H.; Mishra, L.; Noolvi, M.; Karpoormath, R.; Singh Cameotra, S. Synthesis, in Vitro Evaluation, and Molecular Docking Studies of Azetidinones and Thiazolidinones of 2-Amino-5-Cyclopropyl-1,3,4-Thiadiazole as Antibacterial Agents. Arch. Pharm. 2014, 347, 668– 684,  DOI: 10.1002/ardp.201400140
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    52
    Synthesis, in vitro evaluation, and molecular docking studies of azetidinones and thiazolidinones of 2-amino-5-cyclopropyl-1,3,4-thiadiazole as antibacterial agents
    Patel, Harun; Mishra, Lishu; Noolvi, Malleshappa; Karpoormath, Rajshekhar; Singh Cameotra, Swaranjit
    Archiv der Pharmazie (Weinheim, Germany) (2014), 347 (9), 668-684CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In an attempt to find a new class of antimicrobial agents, a series of novel azetidin-2-ones 3a-e and thiazolidin-4-ones 4a-e of 2-amino-5-cyclopropyl-1,3,4-thiadiazole were synthesized. The synthesized compds. were confirmed by m.p., IR, 1H NMR, 13C NMR, and mass spectroscopy. The β-lactam deriv. (3e) was found to be the most potent compd. of the series displaying excellent antibacterial activities against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa with MIC values of 15.60, 31.50, 62.50, and 125 μg/mL, resp., as compared to the pos. control drug ampicillin. Mol. docking studies and detn. of the leakage of UV260- and UV280-absorbing material (nucleic acid material and protein) confirmed that the synthesized compds. inhibit cell wall synthesis by inhibiting PTB (transpeptidase enzyme). Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use, thereby indicating their potential as a drug-like mols.
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  53. 53
    Ito, A.; Nishikawa, T.; Matsumoto, S.; Yoshizawa, H.; Sato, T.; Nakamura, R.; Tsuji, M.; Yamano, Y. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2016, 60, 7396– 7401,  DOI: 10.1128/AAC.01405-16
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    Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa
    Ito, Akinobu; Nishikawa, Toru; Matsumoto, Shuhei; Yoshizawa, Hidenori; Sato, Takafumi; Nakamura, Rio; Tsuji, Masakatsu; Yamano, Yoshinori
    Antimicrobial Agents and Chemotherapy (2016), 60 (12), 7396-7401CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the 3rd-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not obsd. when 1 of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.
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  54. 54
    Zhanel, G. G.; Golden, A. R.; Zelenitsky, S.; Wiebe, K.; Lawrence, C. K.; Adam, H. J.; Idowu, T.; Domalaon, R.; Schweizer, F.; Zhanel, M. A.; Lagacé-Wiens, P. R. S.; Walkty, A. J.; Noreddin, A.; Lynch, J. P., III; Karlowsky, J. A. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 2019, 79, 271– 289,  DOI: 10.1007/s40265-019-1055-2
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    Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli
    Zhanel, George G.; Golden, Alyssa R.; Zelenitsky, Sheryl; Wiebe, Karyn; Lawrence, Courtney K.; Adam, Heather J.; Idowu, Temilolu; Domalaon, Ronald; Schweizer, Frank; Zhanel, Michael A.; Lagace-Wiens, Philippe R. S.; Walkty, Andrew J.; Noreddin, Ayman; Lynch III, Joseph P.; Karlowsky, James A.
    Drugs (2019), 79 (3), 271-289CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
    A review. Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. The primary outcome measure was a composite of clin. cure and microbiol. eradication at the test-of-cure visit, i.e., 7 days after the end of treatment in the microbiol. intent-to-treat population. Secondary outcome measures included microbiol. response per pathogen and per patient at early assessment, end of treatment, TOC, and follow-up; clin. response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concns. of cefiderocol; and the no. of participants with adverse events. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-neg. pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-assocd. pneumonia or healthcare-assocd. pneumonia caused by Gram-neg. pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.
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    Han, S.; Zaniewski, R. P.; Marr, E. S.; Lacey, B. M.; Tomaras, A. P.; Evdokimov, A.; Miller, J. R.; Shanmugasundaram, V. Structural Basis for Effectiveness of Siderophore-Conjugated Monocarbams against Clinically Relevant Strains of Pseudomonas Aeruginosa. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 22002– 22007,  DOI: 10.1073/pnas.1013092107
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    Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa
    Han, Seungil; Zaniewski, Richard P.; Marr, Eric S.; Lacey, Brian M.; Tomaras, Andrew P.; Evdokimov, Artem; Miller, J. Richard; Shanmugasundaram, Veerabahu
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (51), 22002-22007, S22002/1-S22002/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Pseudomonas aeruginosa is an opportunistic Gram-neg. pathogen that causes nosocomial infections for which there are limited treatment options. Penicillin-binding protein PBP3, a key therapeutic target, is an essential enzyme responsible for the final steps of peptidoglycan synthesis and is covalently inactivated by β-lactam antibiotics. Here we disclose the first high resoln. cocrystal structures of the P. aeruginosa PBP3 with both novel and marketed β-lactams. These structures reveal a conformational rearrangement of Tyr532 and Phe533 and a ligand-induced conformational change of Tyr409 and Arg489. The well-known affinity of the monobactam aztreonam for P. aeruginosa PBP3 is due to a distinct hydrophobic arom. wall composed of Tyr503, Tyr532, and Phe533 interacting with the gem-di-Me group. The structure of MC-1, a new siderophore-conjugated monocarbam complexed with PBP3 provides mol. insights for lead optimization. Importantly, we have identified a novel conformation that is distinct to the high-mol.-wt. class B PBP subfamily, which is identifiable by common features such as a hydrophobic arom. wall formed by Tyr503, Tyr532, and Phe533 and the structural flexibility of Tyr409 flanked by two glycine residues. This is also the first example of a siderophore-conjugated triazolone-linked monocarbam complexed with any PBP. Energetic anal. of tightly and loosely held computed hydration sites indicates protein desolvation effects contribute significantly to PBP3 binding, and anal. of hydration site energies allows rank ordering of the second-order acylation rate consts. Taken together, these structural, biochem., and computational studies provide a mol. basis for recognition of P. aeruginosa PBP3 and open avenues for future design of inhibitors of this class of PBPs.
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    Sauvage, E.; Terrak, M. Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials. Antibiotics 2016, 5, 12,  DOI: 10.3390/antibiotics5010012
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    Glycosyltransferases and transpeptidases/penicillin-binding proteins: valuable targets for new antibacterials
    Sauvage, Eric; Terrak, Mohammed
    Antibiotics (Basel, Switzerland) (2016), 5 (1), 12/1-12/27CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
    Peptidoglycan (PG) is an essential macromol. sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clin. useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by β-lactam derivs., but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addn. to traditional β-lactams, other classes of mols. (non-β-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes.
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    Dunn, G. L. Ceftizoxime and Other Third-Generation Cephalosporins: Structure-Activity Relationships. J. Antimicrob. Chemother. 1982, 10, 1– 10,  DOI: 10.1093/jac/10.suppl_C.1
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    Ceftizoxime and other third-generation cephalosporins: structure-activity relationships
    Dunn, G. L.
    Journal of Antimicrobial Chemotherapy (1982), 10 (Suppl. C), 1-10CODEN: JACHDX; ISSN:0305-7453.
    A review with 23 refs. on structure-activity relations of ceftizoxime (I) [68401-81-0] and other aminothiazolyloximino analogs of cephalosporin antibiotics.
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    Kohira, N.; West, J.; Ito, A.; Ito-Horiyama, T.; Nakamura, R.; Sato, T.; Rittenhouse, S.; Tsuji, M.; Yamano, Y. In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains. Antimicrob. Agents Chemother. 2016, 60, 729– 734,  DOI: 10.1128/AAC.01695-15
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    In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains
    Kohira, Naoki; West, Joshua; Ito, Akinobu; Ito-Horiyama, Tsukasa; Nakamura, Rio; Sato, Takafumi; Rittenhouse, Stephen; Tsuji, Masakatsu; Yamano, Yoshinori
    Antimicrobial Agents and Chemotherapy (2016), 60 (2), 729-734CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clin. isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the 1st set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all ≤1 μg/mL, and there were only 8 isolates (1.3%) among these 617 clin. isolates with MIC values of ≥8 μg/mL. In the 2nd set, the MIC values of S-649266 were ≤4 μg/mL against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addn., S-649266 showed MIC values of ≤2 μg/mL against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/mL are uncertain. This is the 1st report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.
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    Portsmouth, S.; van Veenhuyzen, D.; Echols, R.; Machida, M.; Ferreira, J. C. A.; Ariyasu, M.; Tenke, P.; Nagata, T. D. Cefiderocol versus Imipenem-Cilastatin for the Treatment of Complicated Urinary Tract Infections Caused by Gram-Negative Uropathogens: A Phase 2, Randomised, Double-Blind, Non-Inferiority Trial. Lancet Infect. Dis. 2018, 18, 1319– 1328,  DOI: 10.1016/S1473-3099(18)30554-1
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    59
    Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial
    Portsmouth, Simon; van Veenhuyzen, David; Echols, Roger; Machida, Mitsuaki; Ferreira, Juan Camilo Arjona; Ariyasu, Mari; Tenke, Peter; Nagata, Tsutae Den
    Lancet Infectious Diseases (2018), 18 (12), 1319-1328CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)
    We assessed efficacy and safety of cefiderocol vs. imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-neg. infections. Adults (≥18 years) admitted to hospital with a clin. diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h i.v. infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7-14 days. Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). I.v. infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-neg. infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration.
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    Zhang, G.; Meredith, T. C.; Kahne, D. On the Essentiality of Lipopolysaccharide to Gram-Negative Bacteria. Curr. Opin. Microbiol. 2013, 16, 779– 785,  DOI: 10.1016/j.mib.2013.09.007
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    On the essentiality of lipopolysaccharide to Gram-negative bacteria
    Zhang, Ge; Meredith, Timothy C.; Kahne, Daniel
    Current Opinion in Microbiology (2013), 16 (6), 779-785CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
    A review. Lipopolysaccharide is a highly acylated saccharolipid located on the outer leaflet of the outer membrane of Gram-neg. bacteria. Lipopolysaccharide is crit. to maintaining the barrier function preventing the passive diffusion of hydrophobic solutes such as antibiotics and detergents into the cell. Lipopolysaccharide has been considered an essential component for outer membrane biogenesis and cell viability based on pioneering studies in the model Gram-neg. organisms Escherichia coli and Salmonella. With the isolation of lipopolysaccharide-null mutants in Neisseria meningitidis, Moraxella catarrhalis, and most recently in Acinetobacter baumannii, it has become increasingly apparent that lipopolysaccharide is not an essential outer membrane building block in all organisms. We suggest the accumulation of toxic intermediates, misassembly of essential outer membrane porins, and outer membrane stress response pathways that are activated by mislocalized lipopolysaccharide may collectively contribute to the obsd. strain-dependent essentiality of lipopolysaccharide.
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    Kneidinger, B.; Marolda, C.; Graninger, M.; Zamyatina, A.; McArthur, F.; Kosma, P.; Valvano, M. A.; Messner, P. Biosynthesis Pathway of ADP-L-Glycero-Beta-D-Manno-Heptose in Escherichia Coli. J. Bacteriol. 2002, 184, 363– 369,  DOI: 10.1128/JB.184.2.363-369.2002
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    Biosynthesis pathway of ADP-L-glycero-β-D-manno-heptose in Escherichia coli
    Kneidinger, Bernd; Marolda, Cristina; Graninger, Michael; Zamyatina, Alla; McArthur, Fiona; Kosma, Paul; Valvano, Miguel A.; Messner, Paul
    Journal of Bacteriology (2002), 184 (2), 363-369CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
    The steps involved in the biosynthesis of the ADP-L-glycero-β-D-manno-heptose (ADP-L-β-D-heptose) precursor of the inner core lipopolysaccharide (LPS) have not been completely elucidated. In this work, we have purified the enzymes involved in catalyzing the intermediate steps leading to the synthesis of ADP-D-β-D-heptose and have biochem. characterized the reaction products by high-performance anion-exchange chromatog. We have also constructed a deletion in a novel gene, gmhB (formerly yaeD), which results in the formation of an altered LPS core. This mutation confirms that the GmhB protein is required for the formation of ADP-D-β-D-heptose. Our results demonstrate that the synthesis of ADP-D-β-D-heptose in Escherichia coli requires three proteins, GmhA (sedoheptulose 7-phosphate isomerase), HldE (bifunctional D-β-D-heptose 7-phosphate kinase/D-β-D-heptose 1-phosphate adenylyltransferase), and GmhB (D,D-heptose 1,7-bisphosphate phosphatase), as well as ATP and the ketose phosphate precursor sedoheptulose 7-phosphate. A previously characterized epimerase, formerly named WaaD (RfaD) and now renamed HldD, completes the pathway to form the ADP-L-β-D-heptose precursor utilized in the assembly of inner core LPS.
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  62. 62
    Desroy, N.; Moreau, F.; Briet, S.; Le Fralliec, G.; Floquet, S.; Durant, L.; Vongsouthi, V.; Gerusz, V.; Denis, A.; Escaich, S. Towards Gram-Negative Antivirulence Drugs: New Inhibitors of HldE Kinase. Bioorg. Med. Chem. 2009, 17, 1276– 1289,  DOI: 10.1016/j.bmc.2008.12.021
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    Towards Gram-negative antivirulence drugs: New inhibitors of HldE kinase
    Desroy, Nicolas; Moreau, Francois; Briet, Sophia; LeFralliec, Geraldine; Floquet, Stephanie; Durant, Lionel; Vongsouthi, Vanida; Gerusz, Vincent; Denis, Alexis; Escaich, Sonia
    Bioorganic & Medicinal Chemistry (2009), 17 (3), 1276-1289CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Gram-neg. bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochem. assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relation of this series of inhibitors led to highly potent compds.
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    De Leon, G. P.; Elowe, N. H.; Koteva, K. P.; Valvano, M. A.; Wright, G. D. An in Vitro Screen of Bacterial Lipopolysaccharide Biosynthetic Enzymes Identifies an Inhibitor of ADP-Heptose Biosynthesis. Chem. Biol. 2006, 13, 437– 441,  DOI: 10.1016/j.chembiol.2006.02.010
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    An In Vitro Screen of Bacterial Lipopolysaccharide Biosynthetic Enzymes Identifies an Inhibitor of ADP-Heptose Biosynthesis
    De Leon, Gladys P.; Elowe, Nadine H.; Koteva, Kalinka P.; Valvano, Miguel A.; Wright, Gerard D.
    Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (4), 437-441CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
    The lipopolysaccharide (LPS)-rich outer membrane of gram-neg. bacteria provides a protective barrier that insulates these organisms from the action of numerous antibiotics. Breach of the LPS layer can therefore provide access to the cell interior to otherwise impermeant toxic mols. and can expose vulnerable binding sites for immune system components such as complement. Inhibition of LPS biosynthesis, leading to a truncated LPS mol., is an alternative strategy for antibacterial drug development in which this vital cellular structure is weakened. A significant challenge for in vitro screens of small mols. for inhibition of LPS biosynthesis is the difficulty in accessing the complex carbohydrate substrates. We have optimized an assay of the enzymes required for LPS heptose biosynthesis that simultaneously surveys five enzyme activities by using com. available substrates and report its use in a small-mol. screen that identifies an inhibitor of heptose synthesis.
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    Caroff, M.; Karibian, D. Structure of Bacterial Lipopolysaccharides. Carbohydr. Res. 2003, 338, 2431– 2447,  DOI: 10.1016/j.carres.2003.07.010
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    Structure of bacterial lipopolysaccharides
    Caroff, Martine; Karibian, Doris
    Carbohydrate Research (2003), 338 (23), 2431-2447CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
    A review. Bacterial lipopolysaccharides are the major components of the outer surface of Gram-neg. bacteria. They are often of interest in medicine for their immunomodulatory properties. In small amts. they can be beneficial, but in larger amts. they may cause endotoxic shock. Although they share a common architecture, their structural details exert a strong influence on their activity. These mols. comprise: a lipid moiety, called lipid A, which is considered to be the endotoxic component, a glycosidic part consisting of a core of approx. 10 monosaccharides and, in "smooth-type" lipopolysaccharides, a third region, named O-chain, consisting of repetitive subunits of one to eight monosaccharides responsible for much of the immunospecificity of the bacterial cell.
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  65. 65
    Singh, M.; Kumar Singh, S.; Gangwar, M.; Sellamuthu, S.; Nath, G.; Singh, S. K. Design, Synthesis and Mode of Action of Some New 2-(4’-Aminophenyl) Benzothiazole Derivatives as Potent Antimicrobial Agents. Lett. Drug Design Discovery 2016, 13, 429– 437,  DOI: 10.2174/1570180812666150821003220
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    65
    Design, Synthesis and Mode of Action of Some New 2-(4'-aminophenyl) benzothiazole Derivatives as Potent Antimicrobial Agents
    Singh, Meenakshi; Singh, Sudhir Kumar; Gangwar, Mayank; Sellamuthu, Satheeshkumar; Nath, Gopal; Singh, Sushil K.
    Letters in Drug Design & Discovery (2016), 13 (5), 429-437CODEN: LDDDAW; ISSN:1875-628X. (Bentham Science Publishers Ltd.)
    The rapid evolution of antibiotic resistance poses a serious threat to public health. The development of heterocyclic benzothiazole derivs., as efficient and potential agents, has been the focus of antibacterial drug discovery. Present study attempts to evaluate the antibacterial activity and mechanism of action of novel 2-(4'- aminophenyl) benzothiazole derivs. Methods: Antibacterial activity of novel benzothiazole derivs. was evaluated by agar disk diffusion method against a panel of susceptible Gram-pos. and Gram-neg. strains. The mechanism of action was explored by bactericidal kinetics, membrane depolarization, fluorescent assisted cell cytometry and DNA cleavage studies. Results: the authors' findings revealed that compds. A07a and A07b turned out to be the most potent analogs having min. inhibitory concn. values in the range of 3.91-31.2 μg/mL against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli. The new benzothiazole derivs. displayed different modes of action as elucidated by the studies on intact bacterial cells and plasmid DNA. The structure activity relationship studies showed prominent activity of compd. A07a contg. oxime moiety on carbonyl carbon along with less bulky electron releasing and lipophillic group (methoxy and chloro) in Ph ring at C2 position of 2-(4'-aminophenyl) benzothiazole ring system. Conclusion: The potent antibacterial activity of compds. (A07a and A07b) was mediated by membrane perturbing and intracellular mode of actions. These results further validate the use of these derivs. in the treatment of microbial diseases and provide scope for further research.
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    Rajendran, V.; Kalita, P.; Shukla, H.; Kumar, A.; Tripathi, T. Aminoacyl-TRNA Synthetases: Structure, Function, and Drug Discovery. Int. J. Biol. Macromol. 2018, 111, 400– 414,  DOI: 10.1016/j.ijbiomac.2017.12.157
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    Aminoacyl-tRNA synthetases: Structure, function, and drug discovery
    Rajendran, Vijayakumar; Kalita, Parismita; Shukla, Harish; Kumar, Awanish; Tripathi, Timir
    International Journal of Biological Macromolecules (2018), 111 (), 400-414CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)
    Aminoacyl-tRNA synthetases (AARSs) are the enzymes that catalyze the aminoacylation reaction by covalently linking an amino acid to its cognate tRNA in the first step of protein translation. Beyond this classical function, these enzymes are also known to have a role in several metabolic and signaling pathways that are important for cell viability. Study of these enzymes is of great interest to the researchers due to its pivotal role in the growth and survival of an organism. Further, unfolding the interesting structural and functional aspects of these enzymes in the last few years has qualified them as a potential drug target against various diseases. Here we review the classification, function, and the conserved as well the appended structural architecture of these enzymes in detail, including its assocn. with multi-synthetase complexes. We also considered their role in human diseases in terms of mutations and autoantibodies against AARSs. Finally, we have discussed the available inhibitors against AARSs. This review offers comprehensive information on AARSs under a single canopy that would be a good inventory for researchers working in this area.
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    Giegé, R.; Springer, M. Aminoacyl-TRNA Synthetases in the Bacterial World. EcoSal Plus 2016, 7, ESP-0002-2016,  DOI: 10.1128/ecosalplus.ESP-0002-2016
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    Stana, A.; Vodnar, D. C.; Marc, G.; Benedec, D.; Tiperciuc, B.; Tamaian, R.; Oniga, O. Antioxidant Activity and Antibacterial Evaluation of New Thiazolin-4-One Derivatives as Potential Tryptophanyl-TRNA Synthetase Inhibitors. J. Enzyme Inhib. Med. Chem. 2019, 34, 898– 908,  DOI: 10.1080/14756366.2019.1596086
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    Antioxidant activity and antibacterial evaluation of new thiazolin-4-one derivatives as potential tryptophanyl-tRNA synthetase inhibitors
    Stana, Anca; Vodnar, Dan C.; Marc, Gabriel; Benedec, Daniela; Tiperciuc, Brindusa; Tamaian, Radu; Oniga, Ovidiu
    Journal of Enzyme Inhibition and Medicinal Chemistry (2019), 34 (1), 898-908CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
    The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivs. were evaluated for their antibacterial activity by detg. the growth inhibition zone diam., the min. inhibitory concn. (MIC), and the min. bactericidal concn. (MBC), against gram-pos. and gram-neg. bacteria. Compds. , , and expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compds. and displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compds. were subjected to mol. docking on tryptophanyl-tRNA synthetase. Compds. , , and exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compds. was evaluated by four spectrophotometric methods. Thiazolin-4-ones , and presented better antiradical activity than ascorbic acid, trolox and BHT, used as refs.
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    Cascioferro, S.; Totsika, M.; Schillaci, D. Sortase A: An Ideal Target for Anti-Virulence Drug Development. Microb. Pathog. 2014, 77C, 105– 112,  DOI: 10.1016/j.micpath.2014.10.007
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    Oniga, S. D.; Araniciu, C.; Palage, M. D.; Popa, M.; Chifiriuc, M.-C.; Marc, G.; Pirnau, A.; Stoica, C. I.; Lagoudis, I.; Dragoumis, T.; Oniga, O. New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Molecules 2017, 22, 1827,  DOI: 10.3390/molecules22111827
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    New 2-phenylthiazoles as potential sortase a inhibitors: synthesis, biological evaluation and molecular docking
    Oniga, Smaranda Dafina; Araniciu, Catalin; Palage, Mariana Doina; Popa, Marcela; Chifiriuc, Mariana Carmen; Marc, Gabriel; Pirnau, Adrian; Stoica, Cristina Ioana; Lagoudis, Ioannis; Dragoumis, Theodoros; Oniga, Ovidiu
    Molecules (2017), 22 (11), 1827/1-1827/18CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-anal. of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochem. characterization confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compds. have a reduced activity against bacterial cell viability. However, the compds. prevent biofilm formation at very low concns., esp. in the case of E. faecalis. Mol. docking studies performed est. that this is most likely due to the inhibition of Sortase A. The new compds. could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.
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    Parrino, B.; Diana, P.; Cirrincione, G.; Cascioferro, S. Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy. Open Med. Chem. J. 2018, 12, 84– 87,  DOI: 10.2174/1874104501812010084
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    Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy
    Parrino Barbara; Diana Patrizia; Cirrincione Girolamo; Cascioferro Stella
    The open medicinal chemistry journal (2018), 12 (), 84-87 ISSN:1874-1045.
    There is no expanded citation for this reference.
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    Li, X.-H.; Lee, J.-H. Antibiofilm Agents: A New Perspective for Antimicrobial Strategy. J. Microbiol. 2017, 55, 753– 766,  DOI: 10.1007/s12275-017-7274-x
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    Antibiofilm agents: A new perspective for antimicrobial strategy
    Li, Xi-Hui; Lee, Joon-Hee
    Journal of Microbiology (Seoul, Republic of Korea) (2017), 55 (10), 753-766CODEN: JOMIFG; ISSN:1225-8873. (Microbiological Society of Korea)
    Biofilms are complex microbial architectures that attach to surfaces and encase microorganisms in a matrix composed of self-produced hydrated extracellular polymeric substances (EPSs). In biofilms, microorganisms become much more resistant to antimicrobial treatments, harsh environmental conditions, and host immunity. Biofilm formation by microbial pathogens greatly enhances survival in hosts and causes chronic infections that result in persistent inflammation and tissue damages. Currently, it is believed over 80% of chronic infectious diseases are mediated by biofilms, and it is known that conventional antibiotic medications are inadequate at eradicating these biofilm-mediated infections. This situation demands new strategies for biofilm-assocd. infections, and currently, researchers focus on the development of antibiofilm agents that are specific to biofilms, but are nontoxic, because it is believed that this prevents the development of drug resistance. Here, we review the most promising antibiofilm agents undergoing intensive research and development.
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    Cascioferro, S.; Parrino, B.; Petri, G. L.; Cusimano, M. G.; Schillaci, D.; Di Sarno, V.; Musella, S.; Giovannetti, E.; Cirrincione, G.; Diana, P. 2,6-Disubstituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Potent Staphylococcal Biofilm Inhibitors. Eur. J. Med. Chem. 2019, 167, 200– 210,  DOI: 10.1016/j.ejmech.2019.02.007
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    73
    2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent Staphylococcal biofilm inhibitors
    Cascioferro, Stella; Parrino, Barbara; Petri, Giovanna Li; Cusimano, Maria Grazia; Schillaci, Domenico; Di Sarno, Veronica; Musella, Simona; Giovannetti, Elisa; Cirrincione, Girolamo; Diana, Patrizia
    European Journal of Medicinal Chemistry (2019), 167 (), 200-210CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles, compds. I [R = H, Cl, Br; R1 = H, Me; R2 = H, 3-MeO, 4F, etc.] was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-pos. bacterial ref. strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-neg. strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compds., were able to inhibit biofilm formation of the tested Staphylococcal strains showing BIC50 lower than 10 μg/mL. In particular, compds. I [R = H, R1 = H, R2 = 2,5-diMeO; R = H, R1 = Me, R2 = 3-MeO] showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC50 values of 0.5 and 0.8 μg/mL, resp., whereas compd. I [R = Cl, R1 = H, R2 = 2,5-diMeO] was the most potent against S. aureus ATCC 6538, with a BIC50 of 0.3 μg/mL. Remarkably, these compds. showed effects in the early stages of the biofilm formation without affecting the mature biofilm of the same strains and the viability of the planktonic form. Their ability in counteracting a virulence factor (biofilm formation) without interfering with the bacterial growth in the free life form make them novel valuable anti-virulence agents.
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    Qin, Z.; Zhang, J.; Xu, B.; Chen, L.; Wu, Y.; Yang, X.; Shen, X.; Molin, S.; Danchin, A.; Jiang, H.; Qu, D. Structure-Based Discovery of Inhibitors of the YycG Histidine Kinase: New Chemical Leads to Combat Staphylococcus Epidermidis Infections. BMC Microbiol. 2006, 6, 96,  DOI: 10.1186/1471-2180-6-96
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    Structure-based discovery of inhibitors of the YycG histidine kinase: new chemical leads to combat Staphylococcus epidermidis infections
    Qin Zhiqiang; Zhang Jian; Xu Bin; Chen Lili; Wu Yang; Yang Xiaomei; Shen Xu; Molin Soeren; Danchin Antoine; Jiang Hualiang; Qu Di
    BMC microbiology (2006), 6 (), 96 ISSN:.
    BACKGROUND: Coagulase-negative Staphylococcus epidermidis has become a major frequent cause of infections in relation to the use of implanted medical devices. The pathogenicity of S. epidermidis has been attributed to its capacity to form biofilms on surfaces of medical devices, which greatly increases its resistance to many conventional antibiotics and often results in chronic infection. It has an urgent need to design novel antibiotics against staphylococci infections, especially those can kill cells embedded in biofilm. RESULTS: In this report, a series of novel inhibitors of the histidine kinase (HK) YycG protein of S. epidermidis were discovered first using structure-based virtual screening (SBVS) from a small molecular lead-compound library, followed by experimental validation. Of the 76 candidates derived by SBVS targeting of the homolog model of the YycG HATPase_c domain of S. epidermidis, seven compounds displayed significant activity in inhibiting S. epidermidis growth. Furthermore, five of them displayed bactericidal effects on both planktonic and biofilm cells of S. epidermidis. Except for one, the compounds were found to bind to the YycG protein and to inhibit its auto-phosphorylation in vitro, indicating that they are potential inhibitors of the YycG/YycF two-component system (TCS), which is essential in S. epidermidis. Importantly, all these compounds did not affect the stability of mammalian cells nor hemolytic activities at the concentrations used in our study. CONCLUSION: These novel inhibitors of YycG histidine kinase thus are of potential value as leads for developing new antibiotics against infecting staphylococci. The structure-based virtual screening (SBVS) technology can be widely used in screening potential inhibitors of other bacterial TCSs, since it is more rapid and efficacious than traditional screening technology.
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    Pan, B.; Huang, R.; Zheng, L.; Chen, C.; Han, S.; Qu, D.; Zhu, M.; Wei, P. Thiazolidione Derivatives as Novel Antibiofilm Agents: Design, Synthesis, Biological Evaluation, and Structure-Activity Relationships. Eur. J. Med. Chem. 2011, 46, 819– 824,  DOI: 10.1016/j.ejmech.2010.12.014
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    Thiazolidione derivatives as novel antibiofilm agents: Design, synthesis, biological evaluation, and structure-activity relationships
    Pan, Bin; Huang, Renzheng; Zheng, Likang; Chen, Chen; Han, Shiqing; Qu, Di; Zhu, Mingli; Wei, Ping
    European Journal of Medicinal Chemistry (2011), 46 (3), 819-824CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Rational designed novel thiazolidiones were synthesized and evaluated for antibiofilm activity. The active derivs. were not only potent inhibitors of Staphylococcus epidermidis biofilm growth but also efficient antibacterial agents. I showed 4-fold higher activity (6.25 μM) in the biofilms dispersal assay and significantly higher antibacterial activity (MIC 3.125 μM) in comparison to 3-(5-((6-(ethoxycarbonyl)-5-(benzo[1,3]dioxol-5-yl)-3-oxo-7-phenylthiazolo[3,2-a]pyrimidin-2(5H)-ylidene)methyl)furan-2-yl)benzoic acid.
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    Pan, B.; Huang, R.-Z.; Han, S.-Q.; Qu, D.; Zhu, M.-L.; Wei, P.; Ying, H.-J. Design, Synthesis, and Antibiofilm Activity of 2-Arylimino-3-Aryl-Thiazolidine-4-Ones. Bioorg. Med. Chem. Lett. 2010, 20, 2461– 2464,  DOI: 10.1016/j.bmcl.2010.03.013
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    Design, synthesis, and antibiofilm activity of 2-arylimino-3-aryl-thiazolidine-4-ones
    Pan, Bin; Huang, Ren-Zheng; Han, Shi-Qing; Qu, Di; Zhu, Ming-Li; Wei, Ping; Ying, Han-Jie
    Bioorganic & Medicinal Chemistry Letters (2010), 20 (8), 2461-2464CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A series of novel 2-arylimino-3-arylthiazolidin-4-ones was designed, synthesized, and tested for in vitro antibiofilm activity against Staphylococcus epidermidis. Among those tested, some compds. with carboxylic acid groups showed good antibiofilm activity. The structure-activity relationships revealed that incorporation of 2-phenylfuran moiety could greatly enhance antibiofilm activity of thiazolidin-4-one.
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    Rane, R. A.; Sahu, N. U.; Shah, C. P. Synthesis and Antibiofilm Activity of Marine Natural Product-Based 4-Thiazolidinones Derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 7131– 7134,  DOI: 10.1016/j.bmcl.2012.09.073
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    Synthesis and antibiofilm activity of marine natural product-based 4-thiazolidinones derivatives
    Rane, Rajesh A.; Sahu, Niteshkumar U.; Shah, Chetan P.
    Bioorganic & Medicinal Chemistry Letters (2012), 22 (23), 7131-7134CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    4-Thiazolidinones derivs. of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compds. Among the synthesized compds., some showed promising antibiofilm activity. Biol. data revealed that 1,3-thiazolidin-4-one derivs. are more potent antibiofilm agents compared to 1,3-thiazinan-4-ones. Antibiofilm activity of compds. I [Ar = C6H4OMe-4, C6H4NO2-4] (MIC = 0.78 μg/mL, each) was 3-fold superior than std. vancomycin (MIC = 3.125 μg/mL) while activity of compds. I [Ar = C6H3OH-2-OMe-4, C6H3(OH)2-2,5, C6H4F-4, C6H4Cl-4] was 2-fold (MIC = 1.56 μg/mL) against Staphylococcus aureus biofilm. Compds. I [C6H4OMe-4, C6H4NO2-4, C6H3OH-2-OMe-4, C6H3OH-3-OMe-4, C6H3(OH)2-2,5, C6H4F-4, C6H4Cl-4] showed equal antibiofilm activity against Staphylococcus epidermidis compared to std. Vancomycin (MIC = 3.125 μg/mL).
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  78. 78
    Zhao, D.; Chen, C.; Liu, H.; Zheng, L.; Tong, Y.; Qu, D.; Han, S. Biological Evaluation of Halogenated Thiazolo[3,2-a]Pyrimidin-3-One Carboxylic Acid Derivatives Targeting the YycG Histidine Kinase. Eur. J. Med. Chem. 2014, 87, 500– 507,  DOI: 10.1016/j.ejmech.2014.09.096
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    Biological evaluation of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivatives targeting the YycG histidine kinase
    Zhao, Dan; Chen, Chen; Liu, Huayong; Zheng, Likang; Tong, Yao; Qu, Di; Han, Shiqing
    European Journal of Medicinal Chemistry (2014), 87 (), 500-507CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    With an intention to potent inhibitors of YycG histidine kinase, a series of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivs. e. g., I, were synthesized and evaluated for their antibacterial, antibiofilm and hemolytic activities. The majority of the compds. showed good activity against Staphylococcus epidermidis and Staphylococcus aureus, with MIC values of 1.56-6.25 μM, simultaneously presented promising antiobifilm activity against S. epidermidis ATCC35984 at 50 μM. The test of inhibitory activity on YycG kinase suggested the antibacterial activities of these derivs. are based on inhibiting the enzyme activity of the YycG HK domain. The hemolytic activity test suggested these compds. exhibited in vitro antibacterial activity at non-hemolytic concns.
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    Siddiqui, N.; Arya, S. K.; Ahsan, W.; Azad, B. Diverse Biological Activities of Thiazoles: A Retrospect. Int.J. Drug Develop. Res. 2011, 3, 55– 57
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    Diverse biological activities of thiazoles: a retrospect
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    International Journal of Drug Development & Research (2011), 3 (4), 55-67CODEN: IJDDA7; ISSN:0975-9344. (International Journal of Drug Development & Research)
    A review. Many compds. bearing five membered heterocyclic rings in their structure have an extensive spectrum of biol. activities. The search for new biol. active thiazole analogs continues to be an area of intensive investigation in medicinal chem. The present review describes ongoing research in search for new thiazole compds. that can prove useful for the design of future target and development of new drug mol.
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    da Silva, C. M.; da Silva, D. L.; Modolo, L. V.; Alves, R. B.; de Resende, M. A.; Martins, C. V. B. de; de Fátima, Â. Schiff Bases: A Short Review of Their Antimicrobial Activities. J. Advanc. Res. 2011, 2, 1– 8,  DOI: 10.1016/j.jare.2010.05.004
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    More, P. G.; Karale, N. N.; Lawand, A. S.; Narang, N.; Patil, R. H. Synthesis and Anti-Biofilm Activity of Thiazole Schiff Bases. Med. Chem. Res. 2014, 23, 790– 799,  DOI: 10.1007/s00044-013-0672-7
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    Synthesis and anti-biofilm activity of thiazole Schiff bases
    More, Prakash G.; Karale, Netaji N.; Lawand, Anjana S.; Narang, Naina; Patil, Rajendra H.
    Medicinal Chemistry Research (2014), 23 (2), 790-799CODEN: MCREEB; ISSN:1054-2523. (Birkhaeuser Boston)
    A series of thiazole Schiff bases have been synthesized by reacting 4-(o-methoxyphenyl)-2-aminothiazole and R substituted salicylaldehyde (R = H, 3-Me, 4-Me, 5-Me, 3-OMe and 5-Br) or 2-hydroxy-1-naphthaldehyde under microwave irradn. (a green chem. approach). The compds. were characterized by spectral (UV-Vis, IR, 1H NMR, 13C NMR and GC-MS) and thermal analyses, and tested for the evaluation of anti-biofilm activity against Pseudomonas aeruginosa and anti-bacterial activity against Gram pos. (Bacillus subtilis NCIM 2063) and Gram neg. (Escherichia coli NCIM 2931) bacteria. The scanning electron microscopic images of the bacterial surfaces have shown that the Schiff bases have impeded the biofilm formation at 50-100 μg/mL concn., without affecting the growth of the cells (and thus behave as antiquorum sensing agents). Confocal laser scanning microscopy has also confirmed the biofilm inhibition. The anti-biofilm and anti-bacterial activities of the Schiff bases are promising in the design and bio-fabrication of medical devices to combat the biofilm-forming pathogenic organisms.
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    Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent Applications of 1,3-Thiazole Core Structure in the Identification of New Lead Compounds and Drug Discovery. Eur. J. Med. Chem. 2015, 97, 699– 718,  DOI: 10.1016/j.ejmech.2015.04.015
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    Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery
    Ayati, Adile; Emami, Saeed; Asadipour, Ali; Shafiee, Abbas; Foroumadi, Alireza
    European Journal of Medicinal Chemistry (2015), 97 (), 699-718CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. 1,3-Thiazole is one of the most important scaffolds in heterocyclic chem. and drug design and discovery. It is widely found in diverse pharmacol. active substances and in some naturally-occurring compds. Thiazole is a versatile building-block for lead generation, and is easily access of diverse derivs. for subsequent lead optimization. In the recent years, many thiazole derivs. have been synthesized and subjected to varied biol. activities. In this article we intended to review the most important biol. effects of thiazole-based compds. and highlight their roles in new leads identification and drug discovery. This article is also intended to help researches for finding potential future directions on the development of more potent and specific analogs of thiazole-based compds. for various biol. targets.
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    Stefanska, J.; Nowicka, G.; Struga, M.; Szulczyk, D.; Koziol, A. E.; Augustynowicz-Kopec, E.; Napiorkowska, A.; Bielenica, A.; Filipowski, W.; Filipowska, A.; Drzewiecka, A.; Giliberti, G.; Madeddu, S.; Boi, S.; La Colla, P.; Sanna, G. Antimicrobial and Anti-Biofilm Activity of Thiourea Derivatives Incorporating a 2-Aminothiazole Scaffold. Chem. Pharm. Bull. 2015, 63, 225– 236,  DOI: 10.1248/cpb.c14-00837
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    Antimicrobial and Anti-biofilm Activity of Thiourea Derivatives Incorporating a 2-Aminothiazole Scaffold
    Stefanska, Joanna; Nowicka, Grazyna; Struga, Marta; Szulczyk, Daniel; Koziol, Anna Eugenia; Augustynowicz-Kopec, Ewa; Napiorkowska, Agnieszka; Bielenica, Anna; Filipowski, Wojciech; Filipowska, Anna; Drzewiecka, Aleksandra; Giliberti, Gabriele; Madeddu, Silvia; Boi, Stefano; La Colla, Paolo; Sanna, Giuseppina
    Chemical & Pharmaceutical Bulletin (2015), 63 (3), 225-236CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
    A series of new thiourea derivs. of 1,3-thiazole I [R = 2-BrC6H4, cyclohexyl, CH2C6H5, ethoxycarbonyl, etc.] have been synthesized. All obtained compds. were tested in vitro against a no. of microorganisms, including Gram-pos. cocci, Gram-neg. rods and Candida albicans. The compds. I were also tested for their in vitro tuberculostatic activity against the Mycobacterium tuberculosis H37Rv strain, as well as two 'wild' strains isolated from tuberculosis patients. The compds. I (R = 3,4-Cl2C6H3, 3-Cl-4-FC6H3) showed significant inhibition against Gram-pos. cocci (std. strains and hospital strain). The range of MIC values is 2-32 μg/mL. Products I (R = 3,4-Cl2C6H3, 3-Cl-4-FC6H3) effectively inhibited the biofilm formation of both methicillin-resistant and std. strains of S. epidermidis. The halogen atom, esp. at the third position of the Ph group, is significantly important for this antimicrobial activity. Moreover, all obtained compds. resulted in cytotoxicity and antiviral activity on a large set of DNA and RNA viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and other several important human pathogens. The compd. I (R = cyclohexyl) showed activity against HIV-1 and Coxsackievirus type B5. Seven compds. resulted in cytotoxicity against MT-4 cells (CC50<10 μM).
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    Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311– 335,  DOI: 10.1021/np200906s
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    Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
    Newman, David J.; Cragg, Gordon M.
    Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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    Martins, A.; Vieira, H.; Gaspar, H.; Santos, S. Marketed Marine Natural Products in the Pharmaceutical and Cosmeceutical Industries: Tips for Success. Mar. Drugs 2014, 12, 1066– 1101,  DOI: 10.3390/md12021066
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    Marketed marine natural products in the pharmaceutical and cosmeceutical industries: tips for success
    Martins Ana; Vieira Helena; Gaspar Helena; Santos Susana
    Marine drugs (2014), 12 (2), 1066-101 ISSN:.
    The marine environment harbors a number of macro and micro organisms that have developed unique metabolic abilities to ensure their survival in diverse and hostile habitats, resulting in the biosynthesis of an array of secondary metabolites with specific activities. Several of these metabolites are high-value commercial products for the pharmaceutical and cosmeceutical industries. The aim of this review is to outline the paths of marine natural products discovery and development, with a special focus on the compounds that successfully reached the market and particularly looking at the approaches tackled by the pharmaceutical and cosmetic companies that succeeded in marketing those products. The main challenges faced during marine bioactives discovery and development programs were analyzed and grouped in three categories: biodiversity (accessibility to marine resources and efficient screening), supply and technical (sustainable production of the bioactives and knowledge of the mechanism of action) and market (processes, costs, partnerships and marketing). Tips to surpass these challenges are given in order to improve the market entry success rates of highly promising marine bioactives in the current pipelines, highlighting what can be learned from the successful and unsuccessful stories that can be applied to novel and/or ongoing marine natural products discovery and development programs.
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    Cascioferro, S.; Attanzio, A.; Di Sarno, V.; Musella, S.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. New 1,2,4-Oxadiazole Nortopsentin Derivatives with Cytotoxic Activity. Mar. Drugs 2019, 17, 35,  DOI: 10.3390/md17010035
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    New 1,2,4-oxadiazole nortopsentin derivatives with cytotoxic activity
    Cascioferro, Stella; Attanzio, Alessandro; Di Sarno, Veronica; Musella, Simona; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara
    Marine Drugs (2019), 17 (1), 35pp.CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    New analogs of nortopsentin, a natural 2,4-bis(3'-indolyl)imidazole alkaloid, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety and in which a 7-azaindole portion substituted the original indole moiety were efficiently synthesized. Among all derivs., prescreened against the HCT-116 colon rectal carcinoma cell line, the two most active compds. were selected and further investigated in different human tumor cells showing IC50 values in the micromolar and submicromolar range. Flow cytometric anal. of propidium iodide-stained MCF-7 cells demonstrated that both the active derivs. caused cell cycle arrest in the G0-G1 phase. The cell death mechanism induced by the compds. was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and obsd. morphol. evaluation using acridine orange/ethidium bromide double staining. Moreover, further tested on intestinal normal-like differentiated Caco-2 cell line, they exhibited preferential toxicity towards cancer cells.
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    Spanò, V.; Attanzio, A.; Cascioferro, S.; Carbone, A.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs. Mar. Drugs 2016, 14, 226,  DOI: 10.3390/md14120226
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    Synthesis and antitumor activity of new thiazole nortopsentin analogs
    Spano, Virginia; Attanzio, Alessandro; Cascioferro, Stella; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara
    Marine Drugs (2016), 14 (12), 226/1-226/18CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion were conveniently synthesized. Among these, three derivs. showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compds. acted as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population.
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    Parrino, B.; Carbone, A.; Ciancimino, C.; Spanò, V.; Montalbano, A.; Barraja, P.; Cirrincione, G.; Diana, P.; Sissi, C.; Palumbo, M.; Pinato, O.; Pennati, M.; Beretta, G.; Folini, M.; Matyus, P.; Balogh, B.; Zaffaroni, N. Water-Soluble Isoindolo[2,1-a]Quinoxalin-6-Imines: In Vitro Antiproliferative Activity and Molecular Mechanism(s) of Action. Eur. J. Med. Chem. 2015, 94, 149– 162,  DOI: 10.1016/j.ejmech.2015.03.005
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    Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: In vitro antiproliferative activity and molecular mechanism(s) of action
    Parrino, Barbara; Carbone, Anna; Ciancimino, Cristina; Spano, Virginia; Montalbano, Alessandra; Barraja, Paola; Cirrincione, Girolamo; Diana, Patrizia; Sissi, Claudia; Palumbo, Manlio; Pinato, Odra; Pennati, Marzia; Beretta, Giovanni; Folini, Marco; Matyus, Peter; Balogh, Balazs; Zaffaroni, Nadia
    European Journal of Medicinal Chemistry (2015), 94 (), 149-162CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Water-sol. isoindoloquinoxaline (IIQ) imines and the corresponding acetates were conveniently prepd. from the key intermediates 2-(2'-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compds. showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivs., methoxy substituents at positions 3 and 8 or/and 9 were esp. effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were assocd. to IIQ-mediated impairment of tubulin polymn. at pharmacol. significant concns. of tested compds. In addn., impaired DNA topoisomerase I functions and perturbation in telomere architecture were obsd. in cells exposed to micromolar concns. of IIQ derivs. The above results suggest that IIQ derivs. exhibit multi-target cytotoxic activities.
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    Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Lee, T.-H.; Kim, J.-G.; Shin, D.; Sim, C. J.; Shin, J. Antimicrobial Activity and Cytotoxicity of Bis(Indole) Alkaloids from the Sponge Spongosorites Sp. Biol. Pharm. Bull. 2006, 29, 570– 573,  DOI: 10.1248/bpb.29.570
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    Antimicrobial activity and cytotoxicity of bis(indole) alkaloids from the sponge Spongosorites sp.
    Oh, Ki-Bong; Mar, Woongchon; Kim, Sanghee; Kim, Ji-Yun; Lee, Tae-Hoon; Kim, Jae-Gyu; Shin, Daehyun; Sim, Chung J.; Shin, Jongheon
    Biological & Pharmaceutical Bulletin (2006), 29 (3), 570-573CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
    Bis(indole) alkaloids, of the topsentin class (1-4) and hamacanthin class (5-9), isolated from the marine sponge Spongosorites sp. were investigated using several biol. assays. In the evaluation of antimicrobial activity against various strains of bacteria and fungi, compds. of the hamacanthin class exhibited more potent antibacterial activity than those of the topsentin class. Deoxytopsentin (1) and hamacanthin A (5) also exhibited significant antibacterial activity against methicillin-resistant Staphylococcus aureus, with MIC values of less than 12.5 μg/mL. In the antifungal activity test, hamacanthins, esp. hamacanthin A (5), showed potent inhibitory activity against medically important pathogenic fungi. In contrast, all of the topsentins (1-4) were inactive against fungal growth. These compds. (1-9) also exhibited moderate cytotoxicity against cancer cell lines at concns. between 1.1 and >20 μg/mL.
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    Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Oh, M.-N.; Kim, J.-G.; Shin, D.; Sim, C. J.; Shin, J. Bis(Indole) Alkaloids as Sortase A Inhibitors from the Sponge Spongosorites Sp. Bioorg. Med. Chem. Lett. 2005, 15, 4927– 4931,  DOI: 10.1016/j.bmcl.2005.08.021
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    Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp.
    Oh, Ki-Bong; Mar, Woongchon; Kim, Sanghee; Kim, Ji-Yun; Oh, Mi-Na; Kim, Jae-Gyu; Shin, Daehyun; Sim, Chung J.; Shin, Jongheon
    Bioorganic & Medicinal Chemistry Letters (2005), 15 (22), 4927-4931CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A new bis(indole) alkaloid (I) of the hamacanthin class along with the previously reported compds. of the related structural classes, topsentin class and hamacanthin class, was isolated from the marine sponge Spongosorites sp. and their inhibitory activities toward sortase A (SrtA) that play key roles in cell-wall protein anchoring and virulence in Staphylococcus aureus were evaluated. Our studies have identified a series of SrtA inhibitors, providing the basis for further development of potent inhibitors. The preliminary structure-activity relationship, to elucidate the essential structural requirements, has been described. The fibronectin-binding activity data highlight the potential of these compds. for the treatment of S. aureus infections via inhibition of SrtA activity.
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    Gul, W.; Hamann, M. T. Indole Alkaloid Marine Natural Products: An Established Source of Cancer Drug Leads with Considerable Promise for the Control of Parasitic, Neurological and Other Diseases. Life Sci. 2005, 78, 442– 453,  DOI: 10.1016/j.lfs.2005.09.007
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    Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases
    Gul, Waseem; Hamann, Mark T.
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    A review. The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biol. activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacol. activities.
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    A new bis-(indole) alkaloid from a deep-water marine sponge of the genus Spongosorites
    Wright, Amy E.; Pomponi, Shirley A.; Cross, Sue S.; McCarthy, Peter
    Journal of Organic Chemistry (1992), 57 (17), 4772-5CODEN: JOCEAH; ISSN:0022-3263.
    A new bis-(indole)-alkaloid, named dragmacidin d, has been isolated from a deep water marine sponge of the genus Spongosorites. Its structure was detd. through spectroscopic methods, including one and two dimensional NMR spectroscopy. It inhibits the growth of the feline leukemia virus, the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans and the P388 and A549 tumor cell lines.
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    Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.; Jung, J. H. Cytotoxic Bisindole Alkaloids from a Marine Sponge Spongosorites Sp. J. Nat. Prod. 2005, 68, 711– 715,  DOI: 10.1021/np049577a
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    Cytotoxic bisindole alkaloids from a marine sponge Spongosorites sp.
    Bao, Baoquan; Sun, Qishi; Yao, Xinsheng; Hong, Jongki; Lee, Chong-O.; Sim, Chung Ja; Im, Kwang Sik; Jung, Jee H.
    Journal of Natural Products (2005), 68 (5), 711-715CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
    Three new bisindole alkaloids of the hamacanthin class (I-III) and one new bisindole alkaloid of the topsentin class (VI) were isolated along with known bisindole alkaloids (e.g. IV-V) from the MeOH ext. of a marine sponge Spongosorites sp. by bioactivity-guided fractionation. The planar structures were established on the basis of NMR, MS, and IR spectroscopic analyses. Configurations of compds. I-IV were derived from 1H NMR data and optical rotation. Compds. I, IV, V, and isobromodeoxytopsentin showed moderate to significant cytotoxicity against five human tumor cell lines, and compds. I-V showed weak antibacterial activity against clin. isolated methicillin-resistant strains.
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  94. 94
    Sun, H. H.; Sakemi, S.; Gunasekera, S.; Kashman, Y.; Lui, M.; Burres, N.; McCarthy, P. Bis-Indole Imidazole Compounds Which Are Useful Antitumor and Antimicrobial Agents. US 4970226A, 1990.
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  95. 95
    Carbone, A.; Parrino, B.; Cusimano, M. G.; Spanò, V.; Montalbano, A.; Barraja, P.; Schillaci, D.; Cirrincione, G.; Diana, P.; Cascioferro, S. New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation. Mar. Drugs 2018, 16, 274,  DOI: 10.3390/md16080274
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    95
    New thiazole nortopsentin analogues inhibit bacterial biofilm formation
    Carbone, Anna; Parrino, Barbara; Cusimano, Maria Grazia; Spano, Virginia; Montalbano, Alessandra; Barraja, Paola; Schillaci, Domenico; Cirrincione, Girolamo; Diana, Patrizia; Cascioferro, Stella
    Marine Drugs (2018), 16 (8), 274/1-274/15CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    New thiazole nortopsentin analogs I (R = H, OCH3, Br, F; R1 = CH2CH2NHCO2t-Bu, CH2CH2NH2, etc.; R2 = H, Me, etc.) were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-pos. and Gram-neg. pathogens. All compds. were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivs. I (R = H, R1 = CH2CH2NHCO2t-Bu, R2 = H; R = H, R1 = CO2t-Bu, R2 = CH2CH2OCH3) elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40-2.03 μM. The new compds. I showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.
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  96. 96
    Mazmanian, S. K.; Liu, G.; Jensen, E. R.; Lenoy, E.; Schneewind, O. Staphylococcus Aureus Sortase Mutants Defective in the Display of Surface Proteins and in the Pathogenesis of Animal Infections. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 5510– 5515,  DOI: 10.1073/pnas.080520697
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    96
    Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections
    Mazmanian, Sarkis K.; Liu, Gwen; Jensen, Eric R.; Lenoy, Eileen; Schneewind, Olaf
    Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (10), 5510-5515CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Many Gram-pos. bacteria covalently tether their surface adhesins to the cell wall peptidoglycan. We find that surface proteins of Staphylococcus aureus are linked to the cell wall by sortase, an enzyme that cleaves polypeptides at a conserved LPXTG motif. S. aureus mutants lacking sortase fail to process and display surface proteins and are defective in the establishment of infections. Thus, the cell wall envelope of Gram-pos. bacteria represents a surface organelle responsible for interactions with the host environment during the pathogenesis of bacterial infections.
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  97. 97
    Cascioferro, S.; Raffa, D.; Maggio, B.; Raimondi, M. V.; Schillaci, D.; Daidone, G. Sortase A Inhibitors: Recent Advances and Future Perspectives. J. Med. Chem. 2015, 58, 9108– 9123,  DOI: 10.1021/acs.jmedchem.5b00779
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    97
    Sortase A Inhibitors: Recent Advances and Future Perspectives
    Cascioferro, Stella; Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Schillaci, Domenico; Daidone, Giuseppe
    Journal of Medicinal Chemistry (2015), 58 (23), 9108-9123CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Here, we describe the most promising small synthetic org. compds. that act as potent Sortase A inhibitors and cater the potential to be developed as antivirulence drugs. Sortase A is a polypeptide of 206 amino acids, which catalyzes two sequential reactions: (i) thioesterification and (ii) transpeptidation. Sortase A is involved in the process of bacterial adhesion by anchoring LPXTG-contg. proteins to lipid II. Sortase A inhibitors do not affect bacterial growth, but they restrain the virulence of pathogenic bacterial strains, thereby preventing infections caused by Staphylococcus aureus or other Gram-pos. bacteria. The efficacy of the most promising inhibitors needs to be comprehensively evaluated in in vivo models of infection, in order to select compds. eligible for the treatment of bacterial infections in humans.
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  98. 98
    Chen, L.; Yang, D.; Pan, Z.; Lai, L.; Liu, J.; Fang, B.; Shi, S. Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative. Chem. Biol. Drug Des. 2015, 86, 239– 245,  DOI: 10.1111/cbdd.12486
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    98
    Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative
    Chen, Liangzhu; Yang, Dexue; Pan, Zhikun; Lai, Lihong; Liu, Jianhua; Fang, Binghu; Shi, Shuning
    Chemical Biology & Drug Design (2015), 86 (2), 239-245CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
    A series of novel hybrid mols. between sulfonamides and active antimicrobial 14-o-(3-carboxy-phenylsulfide)-mutilin were synthesized, and their in vitro antibacterial activities were evaluated by the broth microdilution. Results indicated that these compds. displayed potent antimicrobial activities in vitro against various drug-susceptible and drug-resistant Gram-pos. bacteria such as Staphylococci and streptococci, including methicillin-resistant Staphylococcus aureus, and mycoplasma. In particular, sulfapyridine analog (6c) exhibited more potent inhibitory activity against Gram-pos. bacteria and mycoplasma, including Staphylococcus aureus (MIC = 0.016-0.063 μg/mL), methicillin-resistant Staphylococcus aureus (MIC = 0.016 μg/mL), Streptococcus pneumoniae (MIC = 0.032-0.063 μg/mL), Mycoplasma gallisepticum (MIC = 0.004 μg/mL), with respect to other synthesized compds. and ref. drugs sulfonamide (MIC = 8-128 μg/mL) and valnemulin (MIC = 0.004-0.5 μg/mL). Furthermore, comparison between MIC values of pleuromutilin-sulfonamide hybrids 6a-f with pleuromutilin parent compd. 3 revealed that these modifications at 14 position side chain of the pleuromutilin with benzene sulfonamide could greatly improve the antibacterial activity esp. against Gram-positives.
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  99. 99
    Klahn, P.; Brönstrup, M. Bifunctional Antimicrobial Conjugates and Hybrid Antimicrobials. Nat. Prod. Rep. 2017, 34, 832– 885,  DOI: 10.1039/C7NP00006E
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    99
    Bifunctional antimicrobial conjugates and hybrid antimicrobials
    Klahn, P.; Broenstrup, M.
    Natural Product Reports (2017), 34 (7), 832-885CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
    A review. Novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. An innovative mol. design strategy for novel antibiotic drugs is based on the hybridization of an antibiotic with a second functional entity. Such conjugates can be grouped into two major categories. In the first category (antimicrobial hybrids), both functional elements of the hybrid exert antimicrobial activity. Due to the dual targeting, resistance development can be significantly impaired, the pharmacokinetic properties can be superior compared to combination therapies with the single antibiotics, and the antibacterial potency is often enhanced in a synergistic manner. In the second category (antimicrobial conjugates), one functional moiety controls the accumulation of the other part of the conjugate, e.g. by mediating an active transport into the bacterial cell or blocking the efflux. This approach is mostly applied to translocate compds. across the cell envelope of Gram-neg. bacteria through membrane-embedded transporters (e.g. siderophore transporters) that provide nutrition and signalling compds. to the cell. Such 'Trojan Horse' approaches can expand the antibacterial activity of compds. against Gram-neg. pathogens, or offer new options for natural products that could not be developed as standalone antibiotics, e.g. due to their toxicity.
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  100. 100
    Gondru, R.; Sirisha, K.; Raj, S.; Gunda, S. K.; Kumar, C. G.; Pasupuleti, M.; Bavantula, R. Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole-Thiazole Hybrids as Antimicrobial and Antibiofilm Agents. ChemistrySelect 2018, 3, 8270– 8276,  DOI: 10.1002/slct.201801391
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    100
    Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole-Thiazole Hybrids as Antimicrobial and Antibiofilm Agents
    Gondru, Ramesh; Sirisha, K.; Raj, Sneha; Gunda, Shravan Kumar; Kumar, C. Ganesh; Pasupuleti, Mukesh; Bavantula, Rajitha
    ChemistrySelect (2018), 3 (28), 8270-8276CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In the present study, a series of novel pyrazole-thiazole hybrids I (R = Ph, 4-MeC6H4, 4-MeOC6H4, etc.) were designed, synthesized and assessed for their in vitro antimicrobial activity against both Gram-pos. and Gram-neg. pathogenic bacterial and fungal strains. Compds. I (R = 4-MeC6H4, 4-BrC6H4, 8-bromocoumarinyl, 6,8-dibromocoumarinyl) exhibited promising inhibitory activity against the tested bacterial strains with min. inhibitory concn. (MIC)/min. bactericidal concn. (MBC) spectrum of 1.9/7.8 μg/mL to 3.9/7.8 μg/mL. The compds. I (R = 4-MeC6H4, 4-MeOC6H4, benzo[f]coumarinyl, 8-bromocoumarinyl) showed their inhibitory potency against various Candida strains with MIC/min. fungicidal concn. (MFC) values of 3.9/7.8 μg/mL. Also, anti-biofilm and toxicity profile of the compds. was also tested. The biofilm inhibition results revealed that the compd. I (R = benzo[f]coumarinyl) exhibited promising activity with an IC50 value of 11.8 μM against S. aureus MTCC 96, while compd. compd. I (R = 8-bromocoumarinyl) showed significant activity against S. aureus MLS16 MTCC 2940, K. planticola MTCC 530 and C. albicans MTCC 3017 with IC50 values of 12, 14 and 16 μM, resp. The present study has emphasized that thiazole-pyrazole hybrids with benzothiazole and coumarin scaffolds can be a novel and potent class of mols. with potential biol. activities.
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  101. 101
    Horwich, A. L.; Farr, G. W.; Fenton, W. A. GroEL-GroES-Mediated Protein Folding. Chem. Rev. 2006, 106, 1917– 1930,  DOI: 10.1021/cr040435v
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    101
    GroEL-GroES-mediated protein folding
    Horwich, Arthur L.; Farr, George W.; Fenton, Wayne A.
    Chemical Reviews (Washington, DC, United States) (2006), 106 (5), 1917-1930CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Chaperonin-mediated folding is an essential ATP-dependent reaction that provides kinetic assistance to the process of protein folding o the native state in a variety of cellular compartments. The Escherichia coli reaction is carried out by a megadalton-sized double ring "machine" consisting of chaperonin GroEL in complex with its co-chaperonin GroES. The binding of GroES to GroEL is ATP-dependent with the nucleotide rapidly and cooperatively binding to 7 sites on the GroEL ring. Here, the catalytic mechanism of GroEL-GroES-mediated protein folding is discussed along with a more detailed consideration of the transition between polypeptide binding in an open ring and productive protein folding in a co-chaperone-encapsulated one. The free energy of binding of the γ-phosphate of ATP functions as a crit. element of the folding trigger. The bulk of existing evidence appears to support a model of GroEL action in which ATP and GroES binding drive major conformational changes in GroEL that simultaneously and immediately release a substrate protein from the apical binding sites and initiate refolding.
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  102. 102
    Johnson, S. M.; Sharif, O.; Mak, P. A.; Wang, H.-T.; Engels, I. H.; Brinker, A.; Schultz, P. G.; Horwich, A. L.; Chapman, E. A Biochemical Screen for GroEL/GroES Inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 786– 789,  DOI: 10.1016/j.bmcl.2013.12.100
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    102
    A biochemical screen for GroEL/GroES inhibitors
    Johnson, Steven M.; Sharif, Orzala; Mak, Puiying Annie; Wang, Hsiao-Ting; Engels, Ingo H.; Brinker, Achim; Schultz, Peter G.; Horwich, Arthur L.; Chapman, Eli
    Bioorganic & Medicinal Chemistry Letters (2014), 24 (3), 786-789CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    High-throughput screening of 700,000 small mols. has identified 235 inhibitors of the GroEL/GroES-mediated refolding cycle. Dose-response anal. of a subset of these hits revealed that 21 compds. are potent inhibitors of GroEL/GroES-mediated refolding (IC50 <10 μM). The screening results presented herein represent the first steps in a broader aim of developing mol. probes to study chaperonin biochem. and physiol.
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  103. 103
    Abdeen, S.; Salim, N.; Mammadova, N.; Summers, C. M.; Frankson, R.; Ambrose, A. J.; Anderson, G. G.; Schultz, P. G.; Horwich, A. L.; Chapman, E.; Johnson, S. M. GroEL/ES Inhibitors as Potential Antibiotics. Bioorg. Med. Chem. Lett. 2016, 26, 3127– 3134,  DOI: 10.1016/j.bmcl.2016.04.089
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    103
    GroEL/ES inhibitors as potential antibiotics
    Abdeen, Sanofar; Salim, Nilshad; Mammadova, Najiba; Summers, Corey M.; Frankson, Rochelle; Ambrose, Andrew J.; Anderson, Gregory G.; Schultz, Peter G.; Horwich, Arthur L.; Chapman, Eli; Johnson, Steven M.
    Bioorganic & Medicinal Chemistry Letters (2016), 26 (13), 3127-3134CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    We recently reported results from a high-throughput screening effort that identified 235 inhibitors of the Escherichia coli GroEL/ES chaperonin system [Bioorg. Med. Chem. Lett.2014, 24, 786]. As the GroEL/ES chaperonin system is essential for growth under all conditions, we reasoned that targeting GroEL/ES with small mol. inhibitors could be a viable antibacterial strategy. Extending from our initial screen, we report here the antibacterial activities of 22 GroEL/ES inhibitors against a panel of Gram-pos. and Gram-neg. bacteria, including E. coli, Bacillus subtilis, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae. GroEL/ES inhibitors were more effective at blocking the proliferation of Gram-pos. bacteria, in particular S. aureus, where lead compds. exhibited antibiotic effects from the low-μM to mid-nM range. While several compds. inhibited the human HSP60/10 refolding cycle, some were able to selectively target the bacterial GroEL/ES system. Despite inhibiting HSP60/10, many compds. exhibited low to no cytotoxicity against human liver and kidney cell lines. Two lead candidates emerged from the panel, that exhibit >50-fold selectivity for inhibiting S. aureus growth compared to liver or kidney cell cytotoxicity. These compds. inhibited drug-sensitive and methicillin-resistant S. aureus strains with potencies comparable to vancomycin, daptomycin, and streptomycin, and are promising candidates to explore for validating the GroEL/ES chaperonin system as a viable antibiotic target.
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  104. 104
    Kim, S.; Lieberman, T. D.; Kishony, R. Alternating Antibiotic Treatments Constrain Evolutionary Paths to Multidrug Resistance. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 14494– 14499,  DOI: 10.1073/pnas.1409800111
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    104
    Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance
    Kim, Seungsoo; Lieberman, Tami D.; Kishony, Roy
    Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (40), 14494-14499CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Alternating antibiotic therapy, in which pairs of drugs are cycled during treatment, has been suggested as a means to inhibit the evolution of de novo resistance while avoiding the toxicity assocd. with more traditional combination therapy. However, it remains unclear under which conditions and by what means such alternating treatments impede the evolution of resistance. Here, the authors tracked multistep evolution of resistance in replicate populations of Staphylococcus aureus during 22 d of continuously increasing single, mixed, and alternating drug treatment. In all three tested drug pairs, the alternating treatment reduced the overall rate of resistance by slowing the acquisition of resistance to one of the two component drugs, sometimes as effectively as mixed treatment. This slower rate of evolution is reflected in the genome-wide mutational profiles; under alternating treatments, bacteria acquire mutations in different genes than under corresponding single-drug treatments. To test whether this obsd. constraint on adaptive paths reflects trade-offs in which resistance to one drug is accompanied by sensitivity to a second drug, we profiled many single-step mutants for cross-resistance. Indeed, the av. cross-resistance of single-step mutants can help predict whether or not evolution was slower in alternating drugs. Together, these results show that despite the complex evolutionary landscape of multidrug resistance, alternating-drug therapy can slow evolution by constraining the mutational paths toward resistance.
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  105. 105
    Yeswanth, S.; Chandra Sekhar, K.; Chaudhary, A.; Sarma, P. V. G. K. Anti-Microbial and Anti-Biofilm Activity of a Novel Dibenzyl (Benzo[d] Thiazol-2-yl-(Hydroxy)-Methyl) Phosphonate by Inducing Protease Expression in Staphylococcus Aureus. Med. Chem. Res. 2018, 27, 785– 795,  DOI: 10.1007/s00044-017-2102-8
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    105
    Anti-microbial and Anti-biofilm activity of a novel Dibenzyl (benzo[d] thiazol-2-yl (hydroxy) methyl) phosphonate by inducing protease expression in Staphylococcus aureus
    Yeswanth, Sthanikam; Chandra Sekhar, Kuruva; Chaudhary, Abhijit; Sarma, Potukuchi Venkata Gurunadha Krishna
    Medicinal Chemistry Research (2018), 27 (3), 785-795CODEN: MCREEB; ISSN:1054-2523. (Springer)
    In the present study a novel Dibenzyl (benzo[d]thiazol-2-yl(hydroxy)methyl) phosphonate (3b) derived from α-Hydroxyphosphonate exhibited anti-Staphylococcus aureus and anti-biofilm properties against penicillin, ampicillin and methicillin-resistant strains of S. aureus. The compd. 3b showed Min. inhibitory concn. (MIC90) at 160 ± 1 μg/mL and LD (LD50) at 80 ± 1 μg/mL. S. aureus growing as planktonic culture shows a formation of aggregates which is the prerequisite for the formation of biofilms, the compd. 3b disrupted aggregates and cleared all the preformed planktonic biofilms and prevented their recurrence. The SDS-PAGE anal. of compd. 3b treated S. aureus showed gradual lysis of total proteins. The zymogram anal. indicated overexpression of proteases which is the principle reason for lysis of total proteins of S. aureus on incubation with compd. 3b. Further, the dot blot anal. indicated complete lysis of Protein-A in the culture filtrate of all the drug-resistant strains of S. aureus a prominent virulence factor and biofilm forming protein. All these features exhibited by compd. 3b makes it as a potential therapeutic mol. in the treatment of S. aureus infections.
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  106. 106
    Hymes, J. P.; Klaenhammer, T. R. Stuck in the Middle: Fibronectin-Binding Proteins in Gram-Positive Bacteria. Front. Microbiol. 2016, 7, 1504,  DOI: 10.3389/fmicb.2016.01504
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    106
    Stuck in the Middle: Fibronectin-Binding Proteins in Gram-Positive Bacteria
    Hymes Jeffrey P; Klaenhammer Todd R
    Frontiers in microbiology (2016), 7 (), 1504 ISSN:1664-302X.
    Fibronectin is a multidomain glycoprotein found ubiquitously in human body fluids and extracellular matrices of a variety of cell types from all human tissues and organs, including intestinal epithelial cells. Fibronectin plays a major role in the regulation of cell migration, tissue repair, and cell adhesion. Importantly, fibronectin also serves as a common target for bacterial adhesins in the gastrointestinal tract. Fibronectin-binding proteins (FnBPs) have been identified and characterized in a wide variety of host-associated bacteria. Single bacterial species can contain multiple, diverse FnBPs. In pathogens, some FnBPs contribute to virulence via host cell attachment, invasion, and interference with signaling pathways. Although FnBPs in commensal and probiotic strains are not sufficient to confer virulence, they are essential for attachment to their ecological niches. Here we describe the interaction between human fibronectin and bacterial adhesins by highlighting the FnBPs of Gram-positive pathogens and commensals. We provide an overview of the occurrence and diversity of FnBPs with a focus on the model pathogenic organisms in which FnBPs are most characterized. Continued investigation of FnBPs is needed to fully understand their divergence and specificity in both pathogens and commensals.
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  107. 107
    Franklin, M. J.; Nivens, D. E.; Weadge, J. T.; Howell, P. L. Biosynthesis of the Pseudomonas Aeruginosa Extracellular Polysaccharides, Alginate, Pel, and Psl. Front. Microbiol. 2011, 2, 167,  DOI: 10.3389/fmicb.2011.00167
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    107
    Biosynthesis of the Pseudomonas aeruginosa Extracellular Polysaccharides, Alginate, Pel, and Psl
    Franklin Michael J; Nivens David E; Weadge Joel T; Howell P Lynne
    Frontiers in microbiology (2011), 2 (), 167 ISSN:.
    Pseudomonas aeruginosa thrives in many aqueous environments and is an opportunistic pathogen that can cause both acute and chronic infections. Environmental conditions and host defenses cause differing stresses on the bacteria, and to survive in vastly different environments, P. aeruginosa must be able to adapt to its surroundings. One strategy for bacterial adaptation is to self-encapsulate with matrix material, primarily composed of secreted extracellular polysaccharides. P. aeruginosa has the genetic capacity to produce at least three secreted polysaccharides; alginate, Psl, and Pel. These polysaccharides differ in chemical structure and in their biosynthetic mechanisms. Since alginate is often associated with chronic pulmonary infections, its biosynthetic pathway is the best characterized. However, alginate is only produced by a subset of P. aeruginosa strains. Most environmental and other clinical isolates secrete either Pel or Psl. Little information is available on the biosynthesis of these polysaccharides. Here, we review the literature on the alginate biosynthetic pathway, with emphasis on recent findings describing the structure of alginate biosynthetic proteins. This information combined with the characterization of the domain architecture of proteins encoded on the Psl and Pel operons allowed us to make predictive models for the biosynthesis of these two polysaccharides. The results indicate that alginate and Pel share certain features, including some biosynthetic proteins with structurally or functionally similar properties. In contrast, Psl biosynthesis resembles the EPS/CPS capsular biosynthesis pathway of Escherichia coli, where the Psl pentameric subunits are assembled in association with an isoprenoid lipid carrier. These models and the environmental cues that cause the cells to produce predominantly one polysaccharide over the others are subjects of current investigation.
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  108. 108
    Colvin, K. M.; Irie, Y.; Tart, C. S.; Urbano, R.; Whitney, J. C.; Ryder, C.; Howell, P. L.; Wozniak, D. J.; Parsek, M. R. The Pel and Psl Polysaccharides Provide Pseudomonas Aeruginosa Structural Redundancy within the Biofilm Matrix. Environ. Microbiol. 2012, 14, 1913– 1928,  DOI: 10.1111/j.1462-2920.2011.02657.x
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    108
    The Pel and Psl polysaccharides provide Pseudomonas aeruginosa structural redundancy within the biofilm matrix
    Colvin, Kelly M.; Irie, Yasuhiko; Tart, Catherine S.; Urbano, Rodolfo; Whitney, John C.; Ryder, Cynthia; Howell, P. Lynne; Wozniak, Daniel J.; Parsek, Matthew R.
    Environmental Microbiology (2012), 14 (8), 1913-1928CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
    Summary : Extracellular polysaccharides comprise a major component of the biofilm matrix. Many species that are adept at biofilm formation have the capacity to produce multiple types of polysaccharides. Pseudomonas aeruginosa produces at least three extracellular polysaccharides, alginate, Pel and Psl, that have been implicated in biofilm development. Non-mucoid strains can use either Pel or Psl as the primary matrix structural polysaccharide. In this study, we evaluated a range of clin. and environmental P. aeruginosa isolates for their dependence on Pel and Psl for biofilm development. Mutational anal. demonstrates that Psl plays an important role in surface attachment for most isolates. However, there was significant strain-to-strain variability in the contribution of Pel and Psl to mature biofilm structure. This anal. led us to propose four classes of strains based upon their Pel and Psl functional and expression profiles. Our data also suggest that Pel and Psl can serve redundant functions as structural scaffolds in mature biofilms. We propose that redundancy could help preserve the capacity to produce a biofilm when exopolysaccharide genes are subjected to mutation. To test this, we used PAO1, a common lab strain that primarily utilizes Psl in the matrix. As expected, a psl mutant strain initially produced a poor biofilm. After extended cultivation, we demonstrate that this strain acquired mutations that upregulated expression of the Pel polysaccharide, demonstrating the utility of having a redundant scaffold exopolysaccharide. Collectively, our studies revealed both unique and redundant roles for two distinct biofilm exopolysaccharides.
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  109. 109
    Colvin, K. M.; Gordon, V. D.; Murakami, K.; Borlee, B. R.; Wozniak, D. J.; Wong, G. C. L.; Parsek, M. R. The Pel Polysaccharide Can Serve a Structural and Protective Role in the Biofilm Matrix of Pseudomonas Aeruginosa. PLoS Pathog. 2011, 7, e1001264  DOI: 10.1371/journal.ppat.1001264
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    109
    The Pel polysaccharide can serve a structural and protective role in the biofilm matrix of Pseudomonas aeruginosa
    Colvin, Kelly M.; Gordon, Vernita D.; Murakami, Keiji; Borlee, Bradley R.; Wozniak, Daniel J.; Wong, Gerard C. L.; Parsek, Matthew R.
    PLoS Pathogens (2011), 7 (1), e1001264CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
    Bacterial extracellular polysaccharides are a key constituent of the extracellular matrix material of biofilms. Pseudomonas aeruginosa is a model organism for biofilm studies and produces three extracellular polysaccharides that have been implicated in biofilm development, alginate, Psl and Pel. Significant work has been conducted on the roles of alginate and Psl in biofilm development, however we know little regarding Pel. In this study, the authors demonstrate that Pel can serve two functions in biofilms. Using a novel assay involving optical tweezers, we demonstrate that Pel is crucial for maintaining cell-to-cell interactions in a PA14 biofilm, serving as a primary structural scaffold for the community. Deletion of pelB resulted in a severe biofilm deficiency. This effect is strain-specific. Loss of Pel prodn. in the lab. strain PAO1 resulted in no difference in attachment or biofilm development; instead Psl proved to be the primary structural polysaccharide for biofilm maturity. Furthermore, the authors demonstrate that Pel plays a second role by enhancing resistance to aminoglycoside antibiotics. This protection occurs only in biofilm populations. Expression of the pel gene cluster and PelF protein levels are enhanced during biofilm growth compared to liq. cultures. Thus, the authors propose that Pel is capable of playing both a structural and a protective role in P. aeruginosa biofilms.
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  110. 110
    Billings, N.; Ramirez Millan, M.; Caldara, M.; Rusconi, R.; Tarasova, Y.; Stocker, R.; Ribbeck, K. The Extracellular Matrix Component Psl Provides Fast-Acting Antibiotic Defense in Pseudomonas Aeruginosa Biofilms. PLoS Pathog. 2013, 9, e1003526  DOI: 10.1371/journal.ppat.1003526
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    110
    The extracellular matrix component Psl provides fast-acting antibiotic defense in Pseudomonas aeruginosa biofilms
    Billings, Nicole; Ramirez Millan, Maria; Caldara, Marina; Rusconi, Roberto; Tarasova, Yekaterina; Stocker, Roman; Ribbeck, Katharina
    PLoS Pathogens (2013), 9 (8), e1003526CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
    Bacteria within biofilms secrete and surround themselves with an extracellular matrix, which serves as a first line of defense against antibiotic attack. Polysaccharides constitute major elements of the biofilm matrix and are implied in surface adhesion and biofilm organization, but their contributions to the resistance properties of biofilms remain largely elusive. Using a combination of static and continuous-flow biofilm expts. we show that Psl, one major polysaccharide in the Pseudomonas aeruginosa biofilm matrix, provides a generic first line of defense toward antibiotics with diverse biochem. properties during the initial stages of biofilm development. Furthermore, we show with mixed-strain expts. that antibiotic-sensitive "non-producing" cells lacking Psl can gain tolerance by integrating into Psl-contg. biofilms. However, non-producers dil. the protective capacity of the matrix and hence, excessive incorporation can result in the collapse of resistance of the entire community. Our data also reveal that Psl mediated protection is extendible to E. coli and S. aureus in co-culture biofilms. Together, our study shows that Psl represents a crit. first bottleneck to the antibiotic attack of a biofilm community early in biofilm development.
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  111. 111
    van Tilburg Bernardes, E.; Charron-Mazenod, L.; Reading, D. J.; Reckseidler-Zenteno, S. L.; Lewenza, S. Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2017, 61, e01997-16  DOI: 10.1128/AAC.01997-16
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    Cascioferro, S.; Cusimano, M. G.; Schillaci, D. Antiadhesion Agents against Gram-Positive Pathogens. Future Microbiol. 2014, 9, 1209– 1220,  DOI: 10.2217/fmb.14.56
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    112
    Antiadhesion agents against Gram-positive pathogens
    Cascioferro, Stella; Cusimano, Maria Grazia; Schillaci, Domenico
    Future Microbiology (2014), 9 (10), 1209-1220CODEN: FMUIAR; ISSN:1746-0913. (Future Medicine Ltd.)
    A review. A fundamental step of Gram-pos. pathogenesis is the bacterial adhesion to the host tissue involving interaction between bacterial surface mols. and host ligands. This review is focused on antivirulence compds. that target Gram-pos. adhesins and on their potential development as therapeutic agents alternative or complementary to conventional antibiotics in the contrast of pathogens. In particular, compds. that target the sortase A, wall theicoic acid inhibitors, carbohydrates able to bind bacterial proteins, and proteins capable of influencing the bacterial adhesion, were described. We further discuss the advantages and disadvantages of this strategy in the development of novel antimicrobials and the future perspective of this research field still at its 1st steps.
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  113. 113
    Berne, C.; Ellison, C. K.; Ducret, A.; Brun, Y. V. Bacterial Adhesion at the Single-Cell Level. Nat. Rev. Microbiol. 2018, 16, 616– 627,  DOI: 10.1038/s41579-018-0057-5
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    113
    Bacterial adhesion at the single-cell level
    Berne, Cecile; Ellison, Courtney K.; Ducret, Adrien; Brun, Yves V.
    Nature Reviews Microbiology (2018), 16 (10), 616-627CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
    The formation of multicellular microbial communities, called biofilms, starts from the adhesion of a few planktonic cells to the surface. The transition from a free-living planktonic lifestyle to a sessile, attached state is a multifactorial process that is detd. by biol., chem. and phys. properties of the environment, the surface and the bacterial cell. The initial weak, reversible interactions between a bacterium and a surface strengthen to yield irreversible adhesion. In this Review, we summarize our understanding of the mechanisms governing bacterial adhesion at the single-cell level, including the phys. forces experienced by a cell before reaching the surface, the first contact with a surface and the transition from reversible to permanent adhesion.
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  114. 114
    Terlizzi, M. E.; Gribaudo, G.; Maffei, M. E. UroPathogenic Escherichia Coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-Antibiotic Antimicrobial Strategies. Front. Microbiol. 2017, 8, 1566,  DOI: 10.3389/fmicb.2017.01566
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    114
    UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies
    Terlizzi Maria E; Gribaudo Giorgio; Maffei Massimo E
    Frontiers in microbiology (2017), 8 (), 1566 ISSN:1664-302X.
    Urinary tract infections (UTIs) are one of the most common pathological conditions in both community and hospital settings. It has been estimated that about 150 million people worldwide develop UTI each year, with high social costs in terms of hospitalizations and medical expenses. Among the common uropathogens associated to UTIs development, UroPathogenic Escherichia coli (UPEC) is the primary cause. UPEC strains possess a plethora of both structural (as fimbriae, pili, curli, flagella) and secreted (toxins, iron-acquisition systems) virulence factors that contribute to their capacity to cause disease, although the ability to adhere to host epithelial cells in the urinary tract represents the most important determinant of pathogenicity. On the opposite side, the bladder epithelium shows a multifaceted array of host defenses including the urine flow and the secretion of antimicrobial substances, which represent useful tools to counteract bacterial infections. The fascinating and intricate dynamics between these players determine a complex interaction system that needs to be revealed. This review will focus on the most relevant components of UPEC arsenal of pathogenicity together with the major host responses to infection, the current approved treatment and the emergence of resistant UPEC strains, the vaccine strategies, the natural antimicrobial compounds along with innovative anti-adhesive and prophylactic approaches to prevent UTIs.
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    Chorell, E.; Pinkner, J. S.; Phan, G.; Edvinsson, S.; Buelens, F.; Remaut, H.; Waksman, G.; Hultgren, S. J.; Almqvist, F. Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity. J. Med. Chem. 2010, 53, 5690– 5695,  DOI: 10.1021/jm100470t
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    115
    Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity
    Chorell, Erik; Pinkner, Jerome S.; Phan, Gilles; Edvinsson, Sofie; Buelens, Floris; Remaut, Han; Waksman, Gabriel; Hultgren, Scott J.; Almqvist, Fredrik
    Journal of Medicinal Chemistry (2010), 53 (15), 5690-5695CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Exptl. evaluation showed that proper substitution of this position affected the biol. activity of the compd. Aryl substituents resulted in pilicides, e.g. I, with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was detd. by X-ray crystallog.
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    Chahales, P.; Hoffman, P. S.; Thanassi, D. G. Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane. Antimicrob. Agents Chemother. 2016, 60, 2028– 2038,  DOI: 10.1128/AAC.02221-15
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    116
    Nitazoxanide inhibits pilus biogenesis by interfering with folding of the usher protein in the outer membrane
    Chahales, Peter; Hoffman, Paul S.; Thanassi, David G.
    Antimicrobial Agents and Chemotherapy (2016), 60 (4), 2028-2038CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Many bacterial pathogens assemble surface fibers termed pili or fimbriae that facilitate attachment to host cells and colonization of host tissues. The chaperone/usher (CU) pathway is a conserved secretion system that is responsible for the assembly of virulence- assocd. pili by many different Gram-neg. bacteria. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and an integral outer membrane (OM) assembly and secretion platform termed the usher. Nitazoxanide (NTZ), an antiparasitic drug, was previously shown to inhibit the function of aggregative adherence fimbriae and type 1 pili assembled by the CU pathway in enteroaggregative Escherichia coli, an important causative agent of diarrhea. We show here that NTZ also inhibits the function of type 1 and P pili from uropathogenic E. coli (UPEC). UPEC is the primary causative agent of urinary tract infections, and type 1 and P pili mediate colonization of the bladder and kidneys, resp. By anal. of the different stages of the CU pilus biogenesis pathway, we show that treatment of bacteria with NTZ causes a redn. in the no. of usher mols. in the OM, resulting in a loss of pilus assembly on the bacterial surface. In addn., we det. that NTZ specifically prevents proper folding of the usher β-barrel domain in the OM. Our findings demonstrate that NTZ is a pilicide with a novel mechanism of action and activity against diverse CU pathways. This suggests that further development of the NTZ scaffold may lead to new antivirulence agents that target the usher to prevent pilus assembly.
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    Opperman, T. J.; Nguyen, S. T. Recent Advances toward a Molecular Mechanism of Efflux Pump Inhibition. Front. Microbiol. 2015, 6, 421,  DOI: 10.3389/fmicb.2015.00421
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    117
    Recent advances toward a molecular mechanism of efflux pump inhibition
    Opperman Timothy J; Nguyen Son T
    Frontiers in microbiology (2015), 6 (), 421 ISSN:1664-302X.
    Multidrug resistance (MDR) in Gram-negative pathogens, such as the Enterobacteriaceae and Pseudomonas aeruginosa, poses a significant threat to our ability to effectively treat infections caused by these organisms. A major component in the development of the MDR phenotype in Gram-negative bacteria is overexpression of Resistance-Nodulation-Division (RND)-type efflux pumps, which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell. Consequently, bacterial efflux pumps are an important target for developing novel antibacterial treatments. Potent efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. Several potent inhibitors of RND-type efflux pump have been reported in the literature, and at least three of these EPI series were optimized in a pre-clinical development program. However, none of these compounds have been tested in the clinic. One of the major hurdles to the development of EPIs has been the lack of biochemical, computational, and structural methods that could be used to guide rational drug design. Here, we review recent reports that have advanced our understanding of the mechanism of action of several potent EPIs against RND-type pumps.
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  118. 118
    Yilmaz, S.; Altinkanat-Gelmez, G.; Bolelli, K.; Guneser-Merdan, D.; Ufuk Over-Hasdemir, M.; Aki-Yalcin, E.; Yalcin, I. Binding Site Feature Description of 2-Substituted Benzothiazoles as Potential AcrAB-TolC Efflux Pump Inhibitors in E. Coli. SAR QSAR Environ. Res. 2015, 26, 853– 871,  DOI: 10.1080/1062936X.2015.1106581
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    118
    Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli
    Yilmaz, S.; Altinkanat-Gelmez, G.; Bolelli, K.; Guneser-Merdan, D.; Ufuk Over-Hasdemir, M.; Aki-Yalcin, E.; Yalcin, I.
    SAR and QSAR in Environmental Research (2015), 26 (10), 853-871CODEN: SQERED; ISSN:1026-776X. (Taylor & Francis Ltd.)
    The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-neg. bacteria. However, although a no. of bacterial RND efflux pump inhibitors have been developed, there has been no clin. available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clin. strain. The results indicated that the BSN compds. did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was obsd. In order to describe the binding site features of these BSN compds. with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calcd. binding energy scores revealed that the tested compds. BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compds. BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compds. are acting as the putative substrates of AcrB.
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    Naaz, F.; Srivastava, R.; Singh, A.; Singh, N.; Verma, R.; Singh, V. K.; Singh, R. K. Molecular Modeling, Synthesis, Antibacterial and Cytotoxicity Evaluation of Sulfonamide Derivatives of Benzimidazole, Indazole, Benzothiazole and Thiazole. Bioorg. Med. Chem. 2018, 26, 3414– 3428,  DOI: 10.1016/j.bmc.2018.05.015
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    119
    Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole
    Naaz, Farha; Srivastava, Ritika; Singh, Anuradha; Singh, Nidhi; Verma, Rajesh; Singh, Vishal K.; Singh, Ramendra K.
    Bioorganic & Medicinal Chemistry (2018), 26 (12), 3414-3428CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    A new series of heterocyclic mols. bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broth diln. method, mols. were found to be highly active (MIC value 50-3.1 μg/mL) against different human pathogens, namely B. cereus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was obsd. during detn. of FIC where mols. were used in combination with ref. drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination - varying concn. of test compds. and 1/2 MIC of ref. drugs or varying concn. of ref. drugs and 1/2 MIC of test compds., was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4-32 times more potent than the test mol. The mols. also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results pos. indicated towards the development of lead antibacterials using the combination approach.
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    Abu-Melha, S.; Edrees, M. M.; Salem, H. H.; Kheder, N. A.; Gomha, S. M.; Abdelaziz, M. R. Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents. Molecules 2019, 24, 539,  DOI: 10.3390/molecules24030539
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    Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents
    Abu-Melha, Sraa; Edrees, Mastoura M.; Salem, Heba H.; Kheder, Nabila A.; Gomha, Sobhi M.; Abdelaziz, Mohamad R.
    Molecules (2019), 24 (3), 539/1-539/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    Two novel series of thiazole-based heterocycles I [R = C(O)Me, CO2Et, C(O)NHPh; Ar = Ph, 4-MeC6H4, 4-ClC6H4, etc.] and II [Ar1 = Ph, 4-MeOC6H4, 4-ClC6H4; Ar2 = Ph, 4-MeC6H4] were synthesized using 1,3-dipolar cycloaddn. reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. Various in vitro biol. assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of compds. I and II. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compds. displayed antitumor activities and compds. I [R = CO2Et; Ar = 2,4-Cl2C6H3] and II [Ar1 = 4-ClC6H4; Ar2 = Ph] showed most potent activity. Compd. I [R = CO2Et; Ar = 4-MeC6H4] most potent activity against S. aureus, B. subtilis and E. coli. Compd I [R = C(O)NHPh; Ar = Ph] exerted the highest antibacterial activity against P. vulgaris.
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    Reddy, N. B.; Zyryanov, G. V.; Reddy, G. M.; Balakrishna, A.; Padmaja, A.; Padmavathi, V.; Reddy, C. S.; Garcia, J. R.; Sravya, G. Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and Pyrazolyl Thiazoles as Potential Antimicrobial Agents. J. Heterocyclic Chem. 2019, 56, 589– 596,  DOI: 10.1002/jhet.3435
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    Franchini, C.; Muraglia, M.; Corbo, F.; Florio, M. A.; Di Mola, A.; Rosato, A.; Matucci, R.; Nesi, M.; van Bambeke, F.; Vitali, C. Synthesis and Biological Evaluation of 2-Mercapto-1,3-Benzothiazole Derivatives with Potential Antimicrobial Activity. Arch. Pharm. 2009, 342, 605– 613,  DOI: 10.1002/ardp.200900092
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    122
    Synthesis and Biological Evaluation of 2-Mercapto-1,3-benzothiazole Derivatives with Potential Antimicrobial Activity
    Franchini, Carlo; Muraglia, Marilena; Corbo, Filomena; Florio, Marco Antonio; Di Mola, Antonia; Rosato, Antonio; Matucci, Rosanna; Nesi, Marta; van Bambeke, Francoise; Vitali, Cesare
    Archiv der Pharmazie (Weinheim, Germany) (2009), 342 (10), 605-613CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compds. with a potent antimicrobial profile, we designed and synthesized low mol. wt. 2-mercaptobenzothiazole derivs. 2a-2l and 3a-3l. Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-pos. and Gram-neg. bacteria strains. The biol. screening identified compds. 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, resp. The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a-3l series. The antibiotic action of compds.2e and 2l was also investigated by testing their activity against some clin. isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our mols. was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compds. by MTS assay against HeLa and MRC-5 cell lines.
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    Cindrić, M.; Perić, M.; Kralj, M.; Martin-Kleiner, I.; David-Cordonnier, M.-H.; Paljetak, H. Č.; Matijašić, M.; Verbanac, D.; Karminski-Zamola, G.; Hranjec, M. Antibacterial and Antiproliferative Activity of Novel 2-Benzimidazolyl- and 2-Benzothiazolyl-Substituted Benzo[b]Thieno-2-Carboxamides. Mol. Diversity 2018, 22, 637– 646,  DOI: 10.1007/s11030-018-9822-7
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    123
    Antibacterial and antiproliferative activity of novel 2-benzimidazolyl- and 2-benzothiazolyl-substituted benzo[b]thieno-2-carboxamides
    Cindric, Maja; Peric, Mihaela; Kralj, Marijeta; Martin-Kleiner, Irena; David-Cordonnier, Marie-Helene; Paljetak, Hana Cipcic; Matijasic, Mario; Verbanac, Donatella; Karminski-Zamola, Grace; Hranjec, Marijana
    Molecular Diversity (2018), 22 (3), 637-646CODEN: MODIF4; ISSN:1381-1991. (Springer)
    Novel (nitro/amino)substituted 2-benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides I and I • HCl [R1 = R2 = H, NH2, NO2; X = NH, S] were designed and synthesized as potential antibacterial agents. The antibacterial activity of these compds. I were evaluated against Gram-pos. (Staphylococcus aureus and Enterococcus faecalis) and Gram-neg. bacteria (Escherichia coli and Moraxella catarrhalis). The most promising antibacterial activity was obsd. for the nitro- and amino-substituted benzimidazole derivs. I [R1 = H; R2 = NH2, NO2; X = NH] and I •Hcl [R1 = H, R2 = NH2, X = NH; R1 = NH2, R2 = H, X = NH] with MICs 2-8 μg/mL. Addnl., compds. with inferior antibacterial activity were further tested for their antiproliferative activity in-vitro against three human cancer cell lines. Amino-substituted benzothiazole hydrochloride salt I [R1 = H, R2 = NH2, X = S] displayed the most pronounced and selective activity against the MCF-7 cell line with an IC50 of 40 nM. Furthermore, DNA binding expts. of selected derivs. indicated that DNA cannot be considered as a primary biol. target for this type of compds.
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  124. 124
    Zha, G.-F.; Leng, J.; Darshini, N.; Shubhavathi, T.; Vivek, H. K.; Asiri, A. M.; Marwani, H. M.; Rakesh, K. P.; Mallesha, N.; Qin, H.-L. Synthesis, SAR and Molecular Docking Studies of Benzo[d]Thiazole-Hydrazones as Potential Antibacterial and Antifungal Agents. Bioorg. Med. Chem. Lett. 2017, 27, 3148– 3155,  DOI: 10.1016/j.bmcl.2017.05.032
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    Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents
    Zha, Gao-Feng; Leng, Jing; Darshini, N.; Shubhavathi, T.; Vivek, H. K.; Asiri, Abdullah M.; Marwani, Hadi M.; Rakesh, K. P.; Mallesha, N.; Qin, Hua-Li
    Bioorganic & Medicinal Chemistry Letters (2017), 27 (14), 3148-3155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A series of new benzo[d]thiazole-hydrazones analogs were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compds. 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the ref. drug chloramphenicol and rifampicin. Compds. 5, 9, 10, 11, 12, 28 and 30 were good antifungal activity compared to the std. drug ketoconazole. A preliminary study of the structure-activity relation (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the Ph ring. The electron donating (OH and OCH3) groups presented in the analogs, increase the antibacterial activity (except compd. 12), interestingly, while the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compd. 19 and 20). In addn., analogs contg. thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliph. analogs (24-26) shown no activities in both bacterial and fungal stains even in high concns. (100 μg/mL). Mol. docking studies were performed for all the synthesized compds. of which compds. 11, 19 and 20 showed the highest glide G-score.
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    Stenger-Smith, J.; Chakraborty, I.; Mascharak, P. K. Cationic Au(I) Complexes with Aryl-Benzothiazoles and Their Antibacterial Activity. J. Inorg. Biochem. 2018, 185, 80– 85,  DOI: 10.1016/j.jinorgbio.2018.05.003
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    125
    Cationic Au(I) complexes with aryl-benzothiazoles and their antibacterial activity
    Stenger-Smith, Jenny; Chakraborty, Indranil; Mascharak, Pradip K.
    Journal of Inorganic Biochemistry (2018), 185 (), 80-85CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    Two cationic Au(I) complexes derived from aryl-benzothiazoles, namely [(PPh3)Au(pbt)](OTf) (1) and [(PPh3)Au(qbt)](OTf) (2) (where pbt=2-(pyridyl)benzothiazole and qbt=(quinolyl)benzothiazole, and OTf-=trifluoromethanesulfonate anion), have been synthesized and structurally characterized by X-ray crystallog. Both complexes exhibit strong antibacterial effects against Gram-neg. bacteria such as Acinetobacter baumannii and Pseudomonas Aeruginosa. Results of examn. of the reactions of 1 and 2 indicate that these cationic Au(I) complexes rapidly cross the bacterial membrane and exert drug action by disrupting cellular function(s) through binding of cytosolic thiol-contg. peptides (such as glutathione) and proteins to the highly reactive (PPh3)Au+ intermediate formed upon in situ dissocn. of pbt or qbt.
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    Maddili, S. K.; Katla, R.; Kannekanti, V. K.; Bejjanki, N. K.; Tuniki, B.; Zhou, C.-H.; Gandham, H. Molecular Interaction of Novel Benzothiazolyl Triazolium Analogues with Calf Thymus DNA and HSA-Their Biological Investigation as Potent Antimicrobial Agents. Eur. J. Med. Chem. 2018, 150, 228– 247,  DOI: 10.1016/j.ejmech.2018.02.056
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    126
    Molecular interaction of novel benzothiazolyl triazolium analogues with calf thymus DNA and HSA-their biological investigation as potent antimicrobial agents
    Maddili, Swetha K.; Katla, Ramesh; Kannekanti, Vijaya Kumar; Bejjanki, Naveen Kumar; Tuniki, Balaraju; Zhou, Cheng-He; Gandham, Himabindu
    European Journal of Medicinal Chemistry (2018), 150 (), 228-247CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    The binding behavior between calf thymus DNA and synthesized benzothiazolyl triazolium derivs. as potent antimicrobial agents was explored by spectroscopic applications together with mol. docking study at the sub-domain IIA, binding site I of human serum albumin (HSA). Most of the synthesized derivs. presented significant antimicrobial inhibition when compared with the clin. Norfloxacin, Chloromycin, and Fluconazole. In particular, compd. 5q (2-phenyl-3-(((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-7-ethoxybenzo[d]imidazo[2,1-b]thiazole) presented efficient anti-Bacillus subtilis, anti-Escherichia coli, anti-Salmonella typhi, and anti-Pseudomonas aeruginosa activity with low MIC values of 2-8 μg/mL which were relatively superior to the ref. drugs. The preliminarily investigation of interaction studies with calf thymus DNA demonstrated that the most active compd. 5q could effectively intercalate into DNA to form 5q-DNA complex. Further investigations revealed that human serum albumin could effectively transport compd. 5q while mol. modeling studies with good docking score showed that hydrophobic interactions as well as hydrogen bonds played a significant role in the interaction of compd. 5q with HSA. In addn., the cytotoxic investigation carried out on four different cancerous cell lines (3 human cell lines and 1 murine cell lines) by MTT assay presented that compd. 5n (2-phenyl-3-(((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-7-ethoxybenzo[d]imidazo[2,1-b]thiazole) is active against MDA cell lines with IC50 values less than 100 μg/mL.
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  127. 127
    Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, C.; Soković, M.; Cirić, A.; Glamoclija, J. Novel 4-Thiazolidinone Derivatives as Potential Antifungal and Antibacterial Drugs. Bioorg. Med. Chem. 2010, 18, 426– 432,  DOI: 10.1016/j.bmc.2009.10.041
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    Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs
    Omar, Kouatli; Geronikaki, Athina; Zoumpoulakis, Panagiotis; Camoutsis, Charalabos; Sokovic, Marina; Ciric, Ana; Glamoclija, Jasmina
    Bioorganic & Medicinal Chemistry (2010), 18 (1), 426-432CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    As part of ongoing studies in developing new antimicrobials, a class of structurally novel 4-thiazolidinone derivs. incorporating three known bioactive nuclei such as thiazole, thiazolidinone and adamantane was synthesized by the multi-step reaction protocol, already reported in the literature. NMR and Mol. Modeling techniques were employed for structure elucidation and Z/E potential isomerism configuration of the analogs. Evaluation of antibacterial and antifungal activity showed that almost all compds. exhibited better results than ref. drugs thus they could be promising candidates for novel drugs.
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    Deep, A.; Jain, S.; Sharma, P. C.; Mittal, S. K.; Phogat, P.; Malhotra, M. Synthesis, Characterization and Antimicrobial Evaluation of 2,5-Disubstituted-4-Thiazolidinone Derivatives. Arabian J. Chem. 2014, 7, 287– 291,  DOI: 10.1016/j.arabjc.2010.10.032
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    128
    Synthesis, characterization and antimicrobial evaluation of 2,5-disubstituted-4-thiazolidinone derivatives
    Deep, Aakash; Jain, Sandeep; Sharma, Prabodh Chander; Mittal, Sanjeev K.; Phogat, Priyanka; Malhotra, Manav
    Arabian Journal of Chemistry (2014), 7 (3), 287-291CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)
    In the present study novel derivs. of 4-thiazolidinone I (Ar = C6H5, 3-BrC6H4, 4-FC6H4; Ar1 = C6H5, 3-O2NC6H4, 4-ClC6H4, 4-CH3OC6H4) were prepd. from biphenyl-4-carboxylic acid and evaluated for their in vitro antimicrobial activity against two gram neg. strains (Escherichia coli and Pseudomonas aeruginosa) and two gram pos. strains (Bacillus subtilis and Staphylococcus aureus) and fungal strains (Candida albicans and Aspergillus niger). The results revealed that all synthesized compds. have significant biol. activity against the tested microorganisms. Among the synthesized derivs. I (Ar = 3-BrC6H4, Ar1 = 3-O2NC6H4; Ar = Ar1 = 3-BrC6H4) were found to be most effective antimicrobial compds.
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    Angapelly, S.; Sri Ramya, P. V.; SunithaRani, R.; Kumar, C. G.; Kamal, A.; Arifuddin, M. Ultrasound Assisted, VOSO4 Catalyzed Synthesis of 4-Thiazolidinones: Antimicrobial Evaluation of Indazole-4-Thiazolidinone Derivatives. Tetrahedron Lett. 2017, 58, 4632– 4637,  DOI: 10.1016/j.tetlet.2017.10.070
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    Ultrasound assisted, VOSO4 catalyzed synthesis of 4-thiazolidinones: Antimicrobial evaluation of indazole-4-thiazolidinone derivatives
    Angapelly, Srinivas; Sri Ramya, P. V.; SunithaRani, Routhu; Kumar, C. Ganesh; Kamal, Ahmed; Arifuddin, Mohammed
    Tetrahedron Letters (2017), 58 (49), 4632-4637CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A simple and expedient multicomponent protocol was developed to synthesize 4-thiazolidinones I (R1 = R5 = R6 = R8 = H, R2 = R3 = R4 = R7 = OCH3; R1 = R2 = R3 = R4 = R5 = R6 = R8 = H, R7 = CF3; R1 = R3 = OCH3, R2 = R4 = R5 = R6 = R8 = H, R7 = F, etc.) by employing VOSO4 as a catalyst under ultrasonic irradn. The significant features of this protocol includes shorter reaction time, high yields, and low catalyst loading, and also the catalyst can be recovered and reused up to next four cycles without significant loss in catalytic activity. All the synthesized novel indazole compds. II (R = 3,4,5-(CH3O)3C6H2, thiophen-2-yl, benzothiazole-2-yl, etc.) were evaluated for their antibacterial and anti-biofilm activities. Compds. II (R = 4-F3CC6H4, 3-F3CC6H4, 4-F3COC6H4) showed promising activity (MIC value of 3.9μg/mL) against K. planticola (MTCC 530). They also exhibited significant bactericidal activity against K. planticola (MTCC 530) (MBC value of 15.6μg/mL). Addnl., II (R = 4-F3CC6H4, 3-F3CC6H4, 4-CF3OC6H4) inhibits biofilm formation (IC50 values ranging between 20.28-20.79μg/mL) in this organism.
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  130. 130
    Pitta, E.; Tsolaki, E.; Geronikaki, A.; Petrović, J.; Glamočlija, J.; Soković, M.; Crespan, E.; Maga, G.; Bhunia, S. S.; Saxena, A. K. 4-Thiazolidinone Derivatives as Potent Antimicrobial Agents: Microwave-Assisted Synthesis, Biological Evaluation and Docking Studies. MedChemComm 2015, 6, 319– 326,  DOI: 10.1039/C4MD00399C
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    130
    4-Thiazolidinone derivatives as potent antimicrobial agents: microwave-assisted synthesis, biological evaluation and docking studies
    Pitta, Eleni; Tsolaki, Evangelia; Geronikaki, Athina; Petrovic, Jovana; Glamoclija, Jasmina; Sokovic, Marina; Crespan, Emmanuele; Maga, Giovanni; Bhunia, Shome S.; Saxena, Anil K.
    MedChemComm (2015), 6 (2), 319-326CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    As a part of the authors' ongoing research in the development of new antimicrobials, herein, the authors report the synthesis of ten compds. which combine three bioactive moieties: thiazole, adamantane and 4-thiazolidinone. Evaluation of their antibacterial activity revealed that the newly synthesized compds. exhibited remarkable growth inhibition of a wide spectrum of Gram-pos. bacteria, Gram-neg. bacteria and fungi. The majority of the compds. displayed greater antibacterial activity than the ref. drugs (ampicillin and streptomycin), while the antifungal activity was significantly higher than that of the ref. drugs bifonazole and ketoconazole. Addnl., the title compds. were screened for HIV-1 reverse transcriptase inhibitory activity, showing no significant activity. Moreover, docking studies were performed to explore possible binding modes at the MurB protein of S. aureus.
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    Ahmed, S.; Zayed, M. F.; El-Messery, S. M.; Al-Agamy, M. H.; Abdel-Rahman, H. M. Design, Synthesis, Antimicrobial Evaluation and Molecular Modeling Study of 1,2,4-Triazole-Based 4-Thiazolidinones. Molecules 2016, 21, 568,  DOI: 10.3390/molecules21050568
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    Design, synthesis, antimicrobial evaluation and molecular modeling study of 1,2,4-triazole-based 4-thiazolidinones
    Ahmed, Sahar; Zayed, Mohamed F.; El-Messery, Shahenda M.; Al-Agamy, Mohamed H.; Abdel-Rahman, Hamdy M.
    Molecules (2016), 21 (5), 568/1-568/17CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivs. I [R = 3-Cl, 4-OMe; R1 = 4-Me, 4-OMe, 4-NO2, 4-F, 4-Cl] was designed and synthesized via reaction of 5-phenyl-3-(benzylideneamino)-2H-1,2,4-triazoles with mercaptoacetic acid. The newly synthesized compds. I were evaluated for their antibacterial and antifungal activities. Among the tested compds., compd. I [R = 4-OMe; R1 = 4-Cl] showed the highest activity against all the tested strains, except P. vulgaris, with MIC 8 μg/mL and 4 μg/mL against S. aureus and C. albicans, resp. Furthermore, Compds. I [R = 3-Cl, R1 = 4-Cl; R = 4-OMe, R1 = 4-Cl; R = 4-OMe, R1 = 4-NO2] demonstrated moderate anti-mycobacterium activity. The binding mode of the synthesized thiazolidinones to bacterial MurB enzyme was also studied. Good interactions between the docked compds. to the MurB active site were obsd. primarily with Asn83, Arg310, Arg188 and Ser82 amino acid residues.
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    Deep, A.; Narasimhan, B.; Lim, S. M.; Ramasamy, K.; Mishra, R. K.; Mani, V. 4-Thiazolidinone Derivatives: Synthesis, Antimicrobial, Anticancer Evaluation and QSAR Studies. RSC Adv. 2016, 6, 109485– 109494,  DOI: 10.1039/C6RA23006G
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    132
    4-Thiazolidinone derivatives: synthesis, antimicrobial, anticancer evaluation and QSAR studies
    Deep, Aakash; Narasimhan, Balasubrmanian; Lim, Siong Meng; Ramasamy, Kalavathy; Mishra, Rakesh Kumar; Mani, Vasudevan
    RSC Advances (2016), 6 (111), 109485-109494CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A series of 4-thiazolidinone derivs. (1-18) was synthesized and tested in vitro for its antimicrobial and anticancer potential. Synthesized compds. were found to be 5 more potent antimicrobial agents than anticancer agents. Anticancer screening results indicated that compd. 13 (IC50 = 15.18 μM) was the most active anticancer agent and was more potent than the std. drug, carboplatin (IC50 > 100 μM). Antimicrobial activity results indicated that 14 was the most active antimicrobial agent (pMICec = 2.14 μM) and may serve as an important lead for the discovery of novel antimicrobial agents. The QSAR studies indicated that the antibacterial and antifungal activities of the synthesized derivs. against different microbial strains were governed by lipophilic parameter, log P, topol. parameter, κα3 and electronic parameters cos E and Nu.E.
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    El-Sayed, E. H.; Fadda, A. A. Synthesis and Antimicrobial Activity of Some Novel Bis Polyfunctional Pyridine, Pyran, and Thiazole Derivatives. J. Heterocyclic Chem. 2018, 55, 2251– 2260,  DOI: 10.1002/jhet.3276
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    Synthesis and Antimicrobial Activity of Some Novel bis Polyfunctional Pyridine, Pyran, and Thiazole Derivatives
    El-Sayed, Elsherbiny H.; Fadda, Ahmed A.
    Journal of Heterocyclic Chemistry (2018), 55 (10), 2251-2260CODEN: JHTCAD; ISSN:1943-5193. (Wiley-Blackwell)
    In continuation of efforts to find a new class of antimicrobial agents, treatment of N,N'-(1,4-phenylene)bis(2-cyanoacetamide) I with formaldehyde and either benzoylacetonitrile or malononitrile to afford pyridine derivs., II and III resp. Similarly, treatment of I with different types of aldehydes afforded benzylidene derivs., followed by the reaction with malononitrile dimer to give polyfunctional pyridine deriv. Moreover, cyanoacetamide was reacted with chalcone, benzylidenemalononitrile, and 1,3-diketone to afford pyran derivs. resp., followed by the reaction with ammonium acetate to afford polyfunctional pyridine derivs., resp. Furthermore, thiazole deriv. was prepd. via treatment of I with elemental sulfur and Ph isothiocyanate. The newly synthesized compds. were evaluated as antimicrobial activities.
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    Devine, S. M.; Mulcair, M. D.; Debono, C. O.; Leung, E. W. W.; Nissink, J. W. M.; Lim, S. S.; Chandrashekaran, I. R.; Vazirani, M.; Mohanty, B.; Simpson, J. S.; Baell, J. B.; Scammells, P. J.; Norton, R. S.; Scanlon, M. J. Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold. J. Med. Chem. 2015, 58, 1205– 1214,  DOI: 10.1021/jm501402x
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    Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold
    Devine, Shane M.; Mulcair, Mark D.; Debono, Cael O.; Leung, Eleanor W. W.; Nissink, J. Willem M.; Lim, San Sui; Chandrashekaran, Indu R.; Vazirani, Mansha; Mohanty, Biswaranjan; Simpson, Jamie S.; Baell, Jonathan B.; Scammells, Peter J.; Norton, Raymond S.; Scanlon, Martin J.
    Journal of Medicinal Chemistry (2015), 58 (3), 1205-1214CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    We have identified a class of mols., known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophys. binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compd. libraries used for high-throughput screening (HTS). This anal. revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties assocd. with optimizing them into a lead compd. makes them, in our opinion, poor scaffolds for fragment libraries.
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    Baell, J. B.; Nissink, J. W. M. Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017—Utility and Limitations. ACS Chem. Biol. 2018, 13, 36– 44,  DOI: 10.1021/acschembio.7b00903
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    Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations
    Baell, Jonathan B.; Nissink, J. Willem M.
    ACS Chemical Biology (2018), 13 (1), 36-44CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    A review on all necessary considerations for the appropriate use of PAINs filters formulated to process hundreds and thousands of compds. in seconds, and identify PAINS in order to exclude them from further anal.
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    Baell, J. B.; Holloway, G. A. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. J. Med. Chem. 2010, 53, 2719– 2740,  DOI: 10.1021/jm901137j
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    136
    New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
    Baell, Jonathan B.; Holloway, Georgina A.
    Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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    Dahlin, J. L.; Nissink, J. W. M.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.; Zhang, Z.; Walters, M. A. PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS. J. Med. Chem. 2015, 58, 2091– 2113,  DOI: 10.1021/jm5019093
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    PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS
    Dahlin, Jayme L.; Nissink, J. Willem M.; Strasser, Jessica M.; Francis, Subhashree; Higgins, LeeAnn; Zhou, Hui; Zhang, Zhiguo; Walters, Michael A.
    Journal of Medicinal Chemistry (2015), 58 (5), 2091-2113CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compds., while understanding the chem. basis for these adverse behaviors often goes unexplored in pursuit of lead compds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compds. Herein, we characterize the chem. basis for assay interference and promiscuous enzymic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compds. (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compds. react covalently with cysteines on multiple proteins. Unfortunately, compds. contg. these chemotypes have been published as screening actives in reputable journals and even touted as chem. probes or preclin. candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compds., guide screening library design, and prevent follow-up on undesirable chem. matter.
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    Forman, H. J.; Davies, K. J. A.; Ursini, F. How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis versus Free Radical Scavenging in Vivo. Free Radical Biol. Med. 2014, 66, 24– 35,  DOI: 10.1016/j.freeradbiomed.2013.05.045
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    How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo
    Forman, Henry J.; Davies, Kelvin J. A.; Ursini, Fulvio
    Free Radical Biology & Medicine (2014), 66 (), 24-35CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    A review. We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiol. evidence for disease prevention by dietary antioxidants and chem. evidence that such compds. react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para-hormesis," provides a means for regulating physiol. nontoxic concns. of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health.
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  139. 139
    Kaminskyy, D.; Kryshchyshyn, A.; Lesyk, R. 5-Ene-4-Thiazolidinones - An Efficient Tool in Medicinal Chemistry. Eur. J. Med. Chem. 2017, 140, 542– 594,  DOI: 10.1016/j.ejmech.2017.09.031
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    139
    5-Ene-4-thiazolidinones - An efficient tool in medicinal chemistry
    Kaminskyy, Danylo; Kryshchyshyn, Anna; Lesyk, Roman
    European Journal of Medicinal Chemistry (2017), 140 (), 542-594CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. The presented review is an attempt to summarize a huge vol. of data on 5-ene-4-thiazolidinones being a widely studied class of small mols. used in modern org. and medicinal chem. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivs., modification of the C5 position of the basic core and synthesis of the target compds. in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacol. profiles of 5-ene derivs. of different 4-thiazolidinone subtypes belonging to hit-, lead-compds., drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compds. (esp. 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compds. (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacol. effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: (i) complication of the fragment in the C5 position; (ii) introduction of the substituents in the N3 position (esp. fragments with carboxylic group or its derivs.); (iii) annealing in complex heterocyclic systems; (iv) combination with other pharmacol. attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compds. with potent pharmacol. application is described. The chem. transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.
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  • Abstract

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    Figure 1

    Figure 1. Schematic representation of the binding mode in GyrB active site of S. aureus of compound 2e. Hydrogen bonds are represented as blue dashed line.

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    Figure 2

    Figure 2. Chemical structures of compounds 3a,b, 4, 5, and chlorobiocin (6).

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    Figure 3

    Figure 3. (A) Bithiazole 5 in G24 active site. Hydrogen bonds are designed as dotted lines; electronic density, contoured at 2σ, is reported as meshed net. (B) Chlorobiocin (6) binding mode into the G24 ATP-binding. (25)Reproduced with permission from ref (25). Copyright 2012 American Chemical Society.

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    Figure 4

    Figure 4. Schematic representation of the binding mode in the E. coli GyrB ATP-binding site of ATP and compound 7a. Hydrogen bonds are represented as green arrows.

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    Figure 5

    Figure 5. Binding mode of compound 10a in the topoisomerase II DNA gyrase active site (1KZN) (A) and binding mode of compound 10a in the E. coli Mur B active site (2Q85) (B). Yellow, van der Waals interactions; blue dashed line, hydrogen bond; blue arrow, π interaction.

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    Figure 6

    Figure 6. Schematic representation of the binding of compound 11d into the active site of S. aureus DNA gyrase. Hydrogen bonds in blue dashed lines.

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    Figure 7

    Figure 7. Graphic representation of the binding mode of compounds 16 and 17. Hydrogen bonds are represented with dashed blue lines, while hydrophobic interactions are in yellow.

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    Figure 8

    Figure 8. Chemical structures of compound 18 and AZD5099(19).

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    Figure 9

    Figure 9. Representative model of the binding mode of compound 18 in complex with S. aureus GyrB (3TTZ) illustrated by ball and stick design.

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    Figure 10

    Figure 10. Representative examples of small molecules with MurB inhibitory activity.

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    Figure 11

    Figure 11. Chemical structures of cefiderocol (24), ceftazidime (25), and cefepime (26).

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    Scheme 1

    Scheme 1. Synthesis of ADP-l-glycero-β-d-manno-heptose from Sedoheptulose-7-phosphate and Its Incorporation into LPS
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    Figure 12

    Figure 12. Chemical structures of compounds 27a,b and 28.

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    Figure 13

    Figure 13. Chemical structures of compounds 29a,b and 30a,b.

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    Figure 14

    Figure 14. Chemical structures of compounds 31a,b and of the known TrpRS inhibitor indolmycin (32).

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    Figure 15

    Figure 15. Chemical structures of compound 34.

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    Figure 16

    Figure 16. Chemical structures of compounds 39a,b, sulfathiazole (40), ceftriaxone (41), aztreonam (42), and compounds 43a,b.

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    Figure 17

    Figure 17. Chemical structures of compounds 47, 48, and 49.

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    Figure 18

    Figure 18. Chemical structures of compounds 50 and nitaxozanide (51).

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    Figure 19

    Figure 19. (A) RND efflux pump structure: integral membrane pump protein (AcrB), an outer membrane (OM) channel protein (TolC), and a periplasmic membrane fusion protein (AcrA). (117) (B) AcrB structure.

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    Figure 20

    Figure 20. Schematic representation of docking poses of compounds 52d, 52f, and 52n in the AcrB binding monomer crystal structure (PDB 2DRD). Hydrogen bonds in green, a π–π interactions in blue, and π–cation interactions in red.

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    Figure 21

    Figure 21. Chemical structures of minocycline (53), doxorubicin (54), rifampicin (55), and erythromycin (56).

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    Figure 22

    Figure 22. Chemical structures of compounds 57a–c, 58a,b, sulfamethoxazole (59), and chloramphenicol (60).

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    Figure 23

    Figure 23. Chemical structure of compound 61.

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    Figure 24

    Figure 24. Chemical structures of compounds 66 and 67.

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    Figure 25

    Figure 25. Chemical structures of compounds 70.

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    Figure 26

    Figure 26. Chemical structure of 76.

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  • References

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      Antimicrobial resistance (AMR) is one of the most serious global public health threats in this century. The first World Health Organization (WHO) Global report on surveillance of AMR, published in April 2014, collected for the first time data from national and international surveillance networks, showing the extent of this phenomenon in many parts of the world and also the presence of large gaps in the existing surveillance. In this review, we focus on antibacterial resistance (ABR), which represents at the moment the major problem, both for the high rates of resistance observed in bacteria that cause common infections and for the complexity of the consequences of ABR. We describe the health and economic impact of ABR, the principal risk factors for its emergence and, in particular, we illustrate the highlights of four antibiotic-resistant pathogens of global concern - Staphylococcus aureus, Klebsiella pneumoniae, non-typhoidal Salmonella and Mycobacterium tuberculosis - for whom we report resistance data worldwide. Measures to control the emergence and the spread of ABR are presented.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3M7pvFylsw%253D%253D&md5=3bf1bde023c0e69c1b9df9e1b3116504
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      Schillaci, D.; Spanò, V.; Parrino, B.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G.; Cascioferro, S. Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms. J. Med. Chem. 2017, 60, 8268– 8297,  DOI: 10.1021/acs.jmedchem.7b00215
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      Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms
      Schillaci, Domenico; Spano, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
      Journal of Medicinal Chemistry (2017), 60 (20), 8268-8297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chem. agents that target the most common mechanisms of antibiotic resistance such as enzymic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here the authors assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. The authors also discuss the potential clin. application of chem. inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymic inhibitors, such as the derivs. of the β-lactamase inhibitor avibactam, are closer to the clinic than other mols. For example, MK-7655, in combination with imipenem, is in clin. development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addn., other mols. targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.
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      Sharma, D.; Bansal, K. K.; Sharma, A.; Pathak, M.; Sharma, P. C. A Brief Literature and Review of Patents on Thiazole Related Derivatives. Curr. Bioact. Compd. 2019, 15, 304– 315,  DOI: 10.2174/1573407214666180827094725
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      A Brief Literature and Review of Patents on Thiazole Related Derivatives
      Sharma, Diksha; Bansal, Kushal K.; Sharma, Archana; Pathak, Meenakshi; Sharma, Prabodh C.
      Current Bioactive Compounds (2019), 15 (3), 304-315CODEN: CBCUBY; ISSN:1573-4072. (Bentham Science Publishers Ltd.)
      Background: Thiazole is widely investigated bioactive scaffold and dynamic tool in medicinal chem. research. Significance of thiazole compds. are well documented as thiazole is an obligatory structure of no. of currently available therapeutics. In spite of that, thiazole derivs. are endowed with myriad biol. activities, such as antiviral, anticancer, antibacterial, antifungal, antimalarial, antiparkinsonian, anti-inflammatory activities and many more. Methods: In recent past, different approaches have been introduced for synthesis of thiazole and related compds. Intrinsic mol. interaction between newly synthesized thiazole compds. and plethora of drug targets/enzymes has rendered discovery of new drug mols. with advances in modes of action. A renewed interest in therapeutic use of thiazole derivs. has been seen among the prospective researchers as exemplified by influx of huge scientific articles and patents. Some important patents of anti-infective and anticancer interest have been addressed appropriately and are presented in tables. Results: This review paper is a contemporary approach on therapeutic/applications of thiazole derivs. by summarizing important patents filed from 2000-2017. The main focus of these patents is on anti-infective and anticancer potential of thiazole based compds. Conclusion: These approaches may provide valuable information for the further design of more active biol. agents through various modifications and derivatizations.
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      Muhammad, Z. A.; Masaret, G. S.; Amin, M. M.; Abdallah, M. A.; Farghaly, T. A. Anti-Inflammatory, Analgesic and Anti-Ulcerogenic Activities of Novel Bis-Thiadiazoles, Bis-Thiazoles and Bis-Formazanes. Med. Chem. 2017, 13, 226– 238,  DOI: 10.2174/1573406412666160920091146
      9
      Anti-inflammatory, Analgesic and Anti-ulcerogenic Activities of Novel bis-thiadiazoles, bis-thiazoles and bis-formazanes
      Muhammad, Zeinab A.; Masaret, Ghada S.; Amin, Mohamed M.; Abdallah, Magda A.; Farghaly, Thoraya A.
      Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 13 (3), 226-238CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
      Indane-1,3-dione, thiazole, bis-thiazole and thiadiazoles rings are very interested moieties in anti-inflammatory and analgesic drugs. The goal of this work is to synthesize new derivs. of bis-thiazoles and bis-1,3,4- thiadiazoles for the investigation of their anti-inflammatory, anti-ulcerogenic and analgesic activities. 1,1'-(1,2-Phenylene)bis(3-phenylthiourea) (1) reacts with a no. of N-aryl arenecarbohydrazonoyl chlorides 2 to give a series of new bis-1,3,4-thiadiazoles 4. Also, reaction of bisthiosemicarbazone of 1,3-indanedione 6 with another type of hydrazonoyl halides namely, N-aryl-2- oxapropanehydrazonoyl chlorides 7 and ethyl-(N-arylhydrazono)chloroacetate 8 in dioxane under reflux in the presence of triethylamine give the resp. bis-thiazole derivs. 9 and 10, resp. The products 9 and 10 can exist in five and seven tautomeric forms for each one. Their actual tautomeric forms were deduced based on electronic absorption data (UV/Vis spectra). Moreover, a series of novel bis-formazans 12 and 13 have been synthesized by reaction of 1,3-dihydrazono-2,3- dihydro-1H-indene (11) with both hydrazonoyl chlorides 7 and 8. The structure of all the novel products was deduced by elemental anal. and spectral data. In addn., the biol. activity of the newly synthesized compds. was evaluated and the results obtained indicate their potency as anti-inflammatory, anti-ulcerogenic and analgesic agents. In this context, we synthesize new derivs. of bis-thiazoles and bis-1,3,4-thiadiazoles as anti-inflammatory, anti-ulcerogenic and analgesic agents.
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    10. 10
      Hosseinzadeh, N.; Seraj, S.; Bakhshi-Dezffoli, M. E.; Hasani, M.; Khoshneviszadeh, M.; Fallah-Bonekohal, S.; Abdollahi, M.; Foroumadi, A.; Shafiee, A. Synthesis and Antidiabetic Evaluation of Benzenesulfonamide Derivatives. Iran J. Pharm. Res. 2013, 12, 325– 330
      10
      Synthesis and antidiabetic evaluation of benzenesulfonamide derivatives
      Hosseinzadeh, Nouraddin; Seraj, Soodeh; Bakhshi-Dezffoli, Mohamad Ebrahim; Hasani, Mohammad; Khoshneviszadeh, Mehdi; Fallah-Bonekohal, Saeed; Abdollahi, Mohammad; Foroumadi, Alireza; Shafiee, Abbas
      Iranian Journal of Pharmaceutical Research (2013), 12 (2), 325-330CODEN: IJPRC9; ISSN:1735-0328. (Shaheed Beheshti University of Medical Sciences and Health Services, School of Pharmacy)
      Novel N-(4-phenylthiazol-2-yl)benzenesulfonamides I (R = MeO, X = H; R = MeO, R1 = 2,5-Cl2C6H3; R = MeO, R1 = 2,4,5-Cl3C6H2; R = MeO, R1 = 4-MeOC6H4; R = MeO, R1 = 4-BrC6H4; R = MeO, R1 = 4-MeC6H4; R = MeO, 4-ClC6H4; R = Cl, R1 = 4-MeC6H4) were synthesized and assayed in-vivo to investigate their antidiabetic activities by a streptozotocin-induced model in rat. These derivs. showed considerable biol. efficacy when compared to glibenclamide as a ref. Some of the compds. were effective, amongst which I (R = MeO, R1 = 2,5-Cl2C6H3) showed more prominent activity at 100 mg/Kg p.o.
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    11. 11
      Morigi, R.; Locatelli, A.; Leoni, A.; Rambaldi, M. Recent Patents on Thiazole Derivatives Endowed with Antitumor Activity. Recent Pat. Anti-Cancer Drug Discovery 2015, 10, 280– 297,  DOI: 10.2174/1574892810666150708110432
      11
      Recent patents on thiazole derivatives endowed with antitumor activity
      Morigi, Rita; Locatelli, Alessandra; Leoni, Alberto; Rambaldi, Mirella
      Recent Patents on Anti-Cancer Drug Discovery (2015), 10 (3), 280-297CODEN: RPADDY; ISSN:1574-8928. (Bentham Science Publishers Ltd.)
      A review. Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chem. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large no. of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compds. useful for the development of new drug mols. It has been divided according to the mol. target and describes the pathways involved in the biol. activities and the structure of the most potent compds., together with the screening results.
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    12. 12
      Pucci, M. J.; Bronson, J. J.; Barrett, J. F.; DenBleyker, K. L.; Discotto, L. F.; Fung-Tomc, J. C.; Ueda, Y. Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics. Antimicrob. Antimicrob. Agents Chemother. 2004, 48, 3697– 3701,  DOI: 10.1128/AAC.48.10.3697-3701.2004
      12
      Antimicrobial evaluation of nocathiacins, a thiazole peptide class of antibiotics
      Pucci, Michael J.; Bronson, Joanne J.; Barrett, John F.; DenBleyker, Kenneth L.; Discotto, Linda F.; Fung-Tomc, Joan C.; Ueda, Yasutsugu
      Antimicrobial Agents and Chemotherapy (2004), 48 (10), 3697-3701CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-pos. bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compds. against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain addnl. structurally related compds. The MIC assay results of BMS-249524 and two more water-sol. derivs., BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-pos. pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Anal. of killing kinetics revealed that these compds. are bactericidal for S. aureus with at least a 3-log10 redn. of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compds. demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-pos. bacterial pathogens.
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    13. 13
      Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. J. Med. Chem. 2015, 58 (11), 4383– 4438,  DOI: 10.1021/jm501853m
      13
      A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
      Beno, Brett R.; Yeung, Kap-Sun; Bartberger, Michael D.; Pennington, Lewis D.; Meanwell, Nicholas A.
      Journal of Medicinal Chemistry (2015), 58 (11), 4383-4438CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Electron deficient, bivalent sulfur atoms have two areas of pos. electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramol. interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a mol. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramol. hydrogen-bonding interaction, appears to be underappreciated by the medicinal chem. community. In this Perspective, we discuss the theor. basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and org. synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermol. interactions between ligand C-S σ* orbitals and proteins are illustrated.
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    14. 14
      Meanwell, N. A. A Synopsis of the Properties and Applications of Heteroaromatic Rings in Medicinal Chemistry. Adv. Heterocycl. Chem. 2017, 123, 245– 361,  DOI: 10.1016/bs.aihch.2016.11.002
      14
      A synopsis of the properties and applications of heteroaromatic rings in medicinal chemistry
      Meanwell, N. A.
      Advances in Heterocyclic Chemistry (2017), 123 (), 245-361CODEN: AHTCAG; ISSN:0065-2725. (Elsevier Inc.)
      A review. Five- and six-membered heteroarom. rings and their benzo-fused homologues are well established as important structural elements in drug design and are well represented in approved drugs. The key properties of these heterocycles that are of interest to medicinal chemists Include lipophilicity, pKa, aromaticity, ionization potential, H-bond acceptor, and H-bond donor (N-H, 0-H, C-H) capability, electron withdrawing effects, dipole values, and bond angles. The judicious and productive application of azoles and azines in drug design requires an understanding of the intrinsic phys. chem. properties of the individual heterocycles and how these interact with substituents. In this article. the key properties of azole and azine heterocycles are summarized followed by a synopsis of applications where some of these factors play a role in drug-target interactions and/or potency.
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    15. 15
      Wolfson, J. S.; Hooper, D. C. The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity in Vitro. Antimicrob. Agents Chemother. 1985, 28, 581– 586,  DOI: 10.1128/AAC.28.4.581
      15
      The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro
      Wolfson, John S.; Hooper, David C.
      Antimicrobial Agents and Chemotherapy (1985), 28 (4), 581-6CODEN: AMACCQ; ISSN:0066-4804.
      A review, with 79 refs., on fluoroquinolones. The mol. structures, antimicrobial activities, and mechanisms of action and resistance are discussed.
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    16. 16
      Reece, R. J.; Maxwell, A. DNA Gyrase: Structure and Function. Crit. Rev. Biochem. Mol. Biol. 1991, 26, 335– 375,  DOI: 10.3109/10409239109114072
      16
      DNA gyrase: structure and function
      Reece, Richard J.; Maxwell, Anthony
      Critical Reviews in Biochemistry and Molecular Biology (1991), 26 (3-4), 335-75CODEN: CRBBEJ; ISSN:1040-9238.
      A review, with 246 refs., summarizing current knowledge of DNA gyrase. DNA gyrase is an essential bacterial enzyme that catalyzes the ATP-dependent neg. supercoiling of double-stranded closed-circular DNA. Gyrase belongs to a class of enzymes known as topoisomerases that are involved in the control of topol. transitions of DNA. The mechanism by which gyrase is able to influence the topol. state of DNA mols. is of inherent interest from an enzymol. standpoint. In addn., much attention has been focused on DNA gyrase as the intracellular target of a no. of antibacterial agents and as a paradigm for other DNA topoisomerases.
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    17. 17
      Pietrusiński, M.; Staczek, P. Bacterial type II topoisomerases as targets for antibacterial drugs. Postepy Biochem. 2006, 52, 271– 282
      17
      Studies of structure and procaryotic functions of type II topoisomerases as an opportunity for development and synthesis of new antibacterial drugs
      Pietrusinski, Michal; Staczek, Pawel
      Postepy Biochemii (2006), 52 (3), 271-282CODEN: PSTBAH; ISSN:0032-5422. (Polskie Towarzystwo Biochemiczne)
      A review. Bacterial type II DNA topoisomerases are essential enzymes for correct genome functioning and cell growth. Gyrase is responsible for maintaining neg. supercoiling of bacterial chromosome, whereas topoisomerase IV acts in disentangling daughter chromosomes following replication. Type II DNA topoisomerases possess an ATP binding site, which can be treated as a target for antibacterial drugs. Resolving crystal structures of protein fragments consisting of an ATP binding site complexed with ADPNP/antibiotics have proven to be valuable for the understanding of the mode of action of existing antibacterial agents and presented new possibilities for novel drug design. Coumarins, quinolones and cyclothialidines are diverse group of antibiotics that interfere with type II DNA topoisomerases, however their mode of action is different. Recently a new class of antibiotics, simociclinones, was characterized. Their mechanism of action towards gyrase is entirely distinct from already known modes of action, therefore demonstrating the potential for development of novel anti-bacterial agents.
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    18. 18
      Bradbury, B. J.; Pucci, M. J. Recent Advances in Bacterial Topoisomerase Inhibitors. Curr. Opin. Pharmacol. 2008, 8, 574– 581,  DOI: 10.1016/j.coph.2008.04.009
      18
      Recent advances in bacterial topoisomerase inhibitors
      Bradbury, Barton J.; Pucci, Michael J.
      Current Opinion in Pharmacology (2008), 8 (5), 574-581CODEN: COPUBK; ISSN:1471-4892. (Elsevier B.V.)
      A review. Bacterial topoisomerase inhibitors continue to be actively developed as clin. antibacterial agents, largely owing to the success of the currently marketed inhibitors, the quinolones, and the increasing resistance to these agents. New quinolone analogs such as isothiazoloquinolones and quinazolinediones show some potential in overcoming this problem. Quinolones linked to other antibacterial agents such as rifamycins and oxazolidinones are designed to overcome both quinolone-specific resistance and resistance to the coupled agents. Novel inhibitors targeting non-quinolone-binding regions of topoisomerase continue to expand beyond the known coumarin class. The benzimidazoles and pyrazoles have shown promise but have been surpassed into the clinic by novel quinolines. Improved screening techniques and high-throughput methods offer new hope of further expanding the chem. space of topoisomerase inhibitors.
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    19. 19
      Ronkin, S. M.; Badia, M.; Bellon, S.; Grillot, A.-L.; Gross, C. H.; Grossman, T. H.; Mani, N.; Parsons, J. D.; Stamos, D.; Trudeau, M.; Wei, Y.; Charifson, P. S. Discovery of Pyrazolthiazoles as Novel and Potent Inhibitors of Bacterial Gyrase. Bioorg. Med. Chem. Lett. 2010, 20, 2828– 2831,  DOI: 10.1016/j.bmcl.2010.03.052
      19
      Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase
      Ronkin, Steven M.; Badia, Michael; Bellon, Steve; Grillot, Anne-Laure; Gross, Christian H.; Grossman, Trudy H.; Mani, Nagraj; Parsons, Jonathan D.; Stamos, Dean; Trudeau, Martin; Wei, Yunyi; Charifson, Paul S.
      Bioorganic & Medicinal Chemistry Letters (2010), 20 (9), 2828-2831CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compds. were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphlococcus aureus GyrB.
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    20. 20
      Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial—Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS Infect. Dis. 2015, 1, 4– 41,  DOI: 10.1021/id500013t
      20
      A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV
      Bisacchi, Gregory S.; Manchester, John I.
      ACS Infectious Diseases (2015), 1 (1), 4-41CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)
      A review. The introduction into clin. practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clin. proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I. In this review, we analyze the historical attempts to discover and develop agents within this class and highlight factors that might have hindered those efforts. Within the last 15 years, however, our tech. understanding of the mol. details of the inhibition of the gyrase and topo IV ATPases, the factors governing resistance development to such inhibitors, and our knowledge of the phys. properties required for robust clin. drug candidates have all matured to the point wherein the industry may now address this mechanism of action with greater confidence. The antibacterial spectrum within this class has recently been extended to begin to include serious Gram neg. pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In spite of this recent tech. progress, adverse economics assocd. with antibacterial R&D over the last 20 years has diminished industry's ability to commit the resources and perseverance needed to bring new-class agents to launch. Consequently, a no. of recent efforts in the ATPase class have been derailed by organizational rather than scientific factors. Nevertheless, within this context we discuss the unique opportunity for the development of ATPase inhibitors of gyrase and topo IV as new-class antibacterial agents with broad spectrum potential.
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    21. 21
      Stokes, N. R.; Thomaides-Brears, H. B.; Barker, S.; Bennett, J. M.; Berry, J.; Collins, I.; Czaplewski, L. G.; Gamble, V.; Lancett, P.; Logan, A.; Lunniss, C. J.; Peasley, H.; Pommier, S.; Price, D.; Smee, C.; Haydon, D. J. Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases. Antimicrob. Agents Chemother. 2013, 57, 5977– 5986,  DOI: 10.1128/AAC.00719-13
      21
      Biological evaluation of benzothiazole ethyl urea inhibitors of bacterial type II topoisomerases
      Stokes Neil R; Thomaides-Brears Helena B; Barker Stephanie; Bennett James M; Berry Joanne; Collins Ian; Czaplewski Lloyd G; Gamble Vicki; Lancett Paul; Logan Alastair; Lunniss Christopher J; Peasley Hilary; Pommier Stephanie; Price Daniel; Smee Carol; Haydon David J
      Antimicrobial agents and chemotherapy (2013), 57 (12), 5977-86 ISSN:.
      The type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml for Streptococcus pneumoniae to 0.25 μg/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 × 10(-10) with compound A and <5.8 × 10(-11) with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.
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    22. 22
      O’Neill, A. J.; Chopra, I. Preclinical Evaluation of Novel Antibacterial Agents by Microbiological and Molecular Techniques. Expert Opin. Invest. Drugs 2004, 13, 1045– 1063,  DOI: 10.1517/13543784.13.8.1045
      22
      Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques
      O'Neill, Alex J.; Chopra, Ian
      Expert Opinion on Investigational Drugs (2004), 13 (8), 1045-1063CODEN: EOIDER; ISSN:1354-3784. (Ashley Publications Ltd.)
      A review. The defining property of an antibacterial agent is its ability to selectively interfere with bacterial growth and/or survival. Consequently, a considerable and crucial part of the preclin. evaluation of any novel antibacterial drug involves judging and characterizing its effects on bacteria in vitro. These crit. stages in drug development are sometimes made to appear somewhat trivial, sandwiched as they are between the highly demanding antibacterial discovery process and the formidable task of demonstrating safety and efficacy in vivo. However, careful biol. evaluation in vitro is key to quantifying and understanding the basis of the antibacterial activity, providing preliminary indications and evaluations of therapeutic potential, assessing the likelihood for the development of bacterial resistance, guiding chem. refinement and assisting subsequent stages of the appraisal of any new antibacterial drug. This review covers concepts in, and strategies for, the in vitro microbiol. and mol. evaluation of antibacterial drug candidates.
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    23. 23
      Axford, L. C.; Agarwal, P. K.; Anderson, K. H.; Andrau, L. N.; Atherall, J.; Barker, S.; Bennett, J. M.; Blair, M.; Collins, I.; Czaplewski, L. G.; Davies, D. T.; Gannon, C. T.; Kumar, D.; Lancett, P.; Logan, A.; Lunniss, C. J.; Mitchell, D. R.; Offermann, D. A.; Palmer, J. T.; Palmer, N.; Pitt, G. R.; Pommier, S.; Price, D.; Narasinga Rao, B.; Saxena, R.; Shukla, T.; Singh, A. K.; Singh, M.; Srivastava, A.; Steele, C.; Stokes, N. R.; Thomaides-Brears, H. B.; Tyndall, E. M.; Watson, D.; Haydon, D. J. Design, Synthesis and Biological Evaluation of α-Substituted Isonipecotic Acid Benzothiazole Analogues as Potent Bacterial Type II Topoisomerase Inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6598– 6603,  DOI: 10.1016/j.bmcl.2013.10.058
      23
      Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors
      Axford, Lorraine C.; Agarwal, Piyush K.; Anderson, Kelly H.; Andrau, Laura N.; Atherall, John; Barker, Stephanie; Bennett, James M.; Blair, Michael; Collins, Ian; Czaplewski, Lloyd G.; Davies, David T.; Gannon, Carlie T.; Kumar, Dushyant; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J.; Mitchell, Dale R.; Offermann, Daniel A.; Palmer, James T.; Palmer, Nicholas; Pitt, Gary R. W.; Pommier, Stephanie; Price, Daniel; Narasinga Rao, B.; Saxena, Rashmi; Shukla, Tarun; Singh, Amit K.; Singh, Mahipal; Srivastava, Anil; Steele, Christopher; Stokes, Neil R.; Thomaides-Brears, Helena B.; Tyndall, Edward M.; Watson, David; Haydon, David J.
      Bioorganic & Medicinal Chemistry Letters (2013), 23 (24), 6598-6603CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The discovery and optimization of a new class of benzothiazole small mols. (e.g. I) that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogs bearing an α-substituent to the carboxylic acid group, resulting in excellent soly. and favorable pharmacokinetic properties.
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    24. 24
      Barančoková, M.; Kikelj, D.; Ilaš, J. Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors. Future Med. Chem. 2018, 10, 1207– 1227,  DOI: 10.4155/fmc-2017-0257
      24
      Recent progress in the discovery and development of DNA gyrase B inhibitors
      Barancokova, Michaela; Kikelj, Danijel; Ilas, Janez
      Future Medicinal Chemistry (2018), 10 (10), 1207-1227CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      A review. New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topol. during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular ref. to Gram-neg. bacteria. Graphical abstr. :.
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    25. 25
      Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-Based Discovery of Substituted 4,5′-Bithiazoles as Novel DNA Gyrase Inhibitors. J. Med. Chem. 2012, 55, 6413– 6426,  DOI: 10.1021/jm300395d
      25
      Structure-Based Discovery of Substituted 4,5'-Bithiazoles as Novel DNA Gyrase Inhibitors
      Brvar, Matjaz; Perdih, Andrej; Renko, Miha; Anderluh, Gregor; Turk, Dusan; Solmajer, Tom
      Journal of Medicinal Chemistry (2012), 55 (14), 6413-6426CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N2-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallog., confirming our initial in silico binding model. Furthermore, the high resoln. of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
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    26. 26
      Liu, J.; Li, X.-W.; Guo, Y.-W. Recent Advances in the Isolation, Synthesis and Biological Activity of Marine Guanidine Alkaloids. Mar. Drugs 2017, 15, 324,  DOI: 10.3390/md15100324
      26
      Recent advances in the isolation, synthesis and biological activity of marine guanidine alkaloids
      Liu, Jin; Li, Xu-Wen; Guo, Yue-Wei
      Marine Drugs (2017), 15 (10), 324/1-324/19CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      Marine organisms are prolific resources of guanidine-contg. natural products with intriguing structures and promising biol. activities. These mols. have therefore attracted the attention of chemists and biologists for their further studies towards potential drug leads. This review focused on the guanidine alkaloids derived from marine sources and discussed the recent progress on their isolation, synthesis and biol. activities, covering the literature from the year 2010 to the present.
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    27. 27
      Netz, N.; Opatz, T. Marine Indole Alkaloids. Mar. Drugs 2015, 13, 4814– 4914,  DOI: 10.3390/md13084814
      27
      Marine indole alkaloids
      Netz, Natalie; Opatz, Till
      Marine Drugs (2015), 13 (8), 4814-4914CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      Marine indole alkaloids comprise a large and steadily growing group of secondary metabolites. Their diverse biol. activities make many compds. of this class attractive starting points for pharmaceutical development. Several marine-derived indoles were found to possess cytotoxic, antineoplastic, antibacterial and antimicrobial activities, in addn. to the action on human enzymes and receptors. The newly isolated indole alkaloids of marine origin since the last comprehensive review in 2003 are reported, and biol. aspects will be discussed.
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    28. 28
      Parrino, B.; Attanzio, A.; Spanò, V.; Cascioferro, S.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Diana, P.; Cirrincione, G.; Carbone, A. Synthesis, Antitumor Activity and CDK1 Inhibiton of New Thiazole Nortopsentin Analogues. Eur. J. Med. Chem. 2017, 138, 371– 383,  DOI: 10.1016/j.ejmech.2017.06.052
      28
      Synthesis, antitumor activity and CDK1 inhibition of new thiazole nortopsentin analogues
      Parrino, Barbara; Attanzio, Alessandro; Spano, Virginia; Cascioferro, Stella; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Diana, Patrizia; Cirrincione, Girolamo; Carbone, Anna
      European Journal of Medicinal Chemistry (2017), 138 (), 371-383CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A new series of thiazole nortopsentin analogs was conveniently synthesized with fair overall yields. The antiproliferative activity of the new derivs. was tested against different human tumor cell lines of the NCI full panel. Four of them, e. g., I, showed good antitumor activity with GI50 values from micro to nanomolar level. The mechanism of the antiproliferative effect of these derivs., was pro-apoptotic, being assocd. with externalization of plasma membrane phosphatidylserine and DNA fragmentation. The most active and selective of the new thiazoles confined viable cells in G2/M phase and markedly inhibited in vitro CDK1 activity.
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    29. 29
      Parrino, B.; Schillaci, D.; Carnevale, I.; Giovannetti, E.; Diana, P.; Cirrincione, G.; Cascioferro, S. Synthetic Small Molecules as Anti-Biofilm Agents in the Struggle against Antibiotic Resistance. Eur. J. Med. Chem. 2019, 161, 154– 178,  DOI: 10.1016/j.ejmech.2018.10.036
      29
      Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance
      Parrino, Barbara; Schillaci, Domenico; Carnevale, Ilaria; Giovannetti, Elisa; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella
      European Journal of Medicinal Chemistry (2019), 161 (), 154-178CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. Biofilm formation significantly contributes to microbial survival in hostile environments and it is currently considered a key virulence factor for pathogens responsible for serious chronic infections. In the last decade many efforts have been made to identify new agents able to modulate bacterial biofilm life cycle, and many compds. have shown interesting activities in inhibiting biofilm formation or in dispersing pre-formed biofilms. However, only a few of these compds. were tested using in vivo models for their clin. significance. Contrary to conventional antibiotics, most of the anti-biofilm compds. act as anti-virulence agents as they do not affect bacterial growth. In this review we selected the most relevant literature of the last decade, focusing on the development of synthetic small mols. able to prevent bacterial biofilm formation or to eradicate pre-existing biofilms of clin. relevant Gram-pos. and Gram-neg. pathogens. In addn., we provide a comprehensive list of the possible targets to counteract biofilm formation and development, as well as a detailed discussion the advantages and disadvantages of the different current biofilm-targeting strategies.
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    30. 30
      Ballard, T. E.; Richards, J. J.; Aquino, A.; Reed, C. S.; Melander, C. Antibiofilm activiy of a diverse oroidin library, generated through reductive acylation. J. Org. Chem. 2009, 74, 1755– 1758,  DOI: 10.1021/jo802260t
      30
      Antibiofilm Activity of a Diverse Oroidin Library Generated through Reductive Acylation
      Ballard, T. Eric; Richards, Justin J.; Aquino, Arianexys; Reed, Catherine S.; Melander, Christian
      Journal of Organic Chemistry (2009), 74 (4), 1755-1758CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      A diverse 20-compd. library of analogs, e.g. I, based on the marine alkaloid oroidin were synthesized via a reductive acylation strategy. The final target was then assayed for inhibition and dispersion activity against common proteobacteria known to form biofilms. This methodol. represents a significant improvement over the generality of known methods to acylate substrates contg. 2-aminoimidazoles and has the potential to have broad application to the synthesis of more advanced oroidin family members and their corresponding analogs.
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    31. 31
      Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, C. Synthesis and Screening of an Oroidin Library against Pseudomonas Aeruginosa Biofilms. ChemBioChem 2008, 9, 1267– 1279,  DOI: 10.1002/cbic.200700774
      31
      Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms
      Richards, Justin J.; Ballard, T. Eric; Huigens, Robert W., III; Melander, Christian
      ChemBioChem (2008), 9 (8), 1267-1279CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A 50-compd. library based on the marine natural product oroidin was synthesized and assayed for anti-biofilm activity against PAO1 and PA14, two strains of the medically relevant γ-proteobacterium Pseudomonas aeruginosa. Through structure-activity relationship (SAR) anal. of analogs based on the oroidin template, several conclusion can be drawn as to what structural properties of the synthetic derivs. are necessary to elicit a biol. response. Notably, the most active analogs identified were those that contained a 2-aminoimidazole (2-Al) motif and a dibrominated pyrrolecarboxamide subunit. Here we disclose the synthesis and subsequently detd. biol. activity of this unique class of compds. as inhibitors of biofilm formation that have no direct antibiotic effect.
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    32. 32
      Hodnik, Ž.; Łoś, J. M.; Žula, A.; Zidar, N.; Jakopin, Ž.; Łoś, M.; Sollner Dolenc, M.; Ilaš, J.; Wȩgrzyn, G.; Peterlin Mašič, L.; Kikelj, D. Inhibition of Biofilm Formation by Conformationally Constrained Indole-Based Analogues of the Marine Alkaloid Oroidin. Bioorg. Med. Chem. Lett. 2014, 24, 2530– 2534,  DOI: 10.1016/j.bmcl.2014.03.094
      32
      Inhibition of biofilm formation by conformationally constrained indole-based analogs of the marine alkaloid oroidin
      Hodnik, Ziga; Los, Joanna M.; Zula, Ales; Zidar, Nace; Jakopin, Ziga; Los, Marcin; Sollner Dolenc, Marija; Ilas, Janez; Wegrzyn, Grzegorz; Peterlin Masic, Lucija; Kikelj, Danijel
      Bioorganic & Medicinal Chemistry Letters (2014), 24 (11), 2530-2534CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The authors describe indole-based analogs of oroidin as a novel class of 2-aminoimidazole-based inhibitors of methicillin-resistant Staphylococcus aureus biofilm formation and of 2-aminoimidazole-based inhibitors of Streptococcus mutans biofilm formation. This study highlighted the indole moiety as a dibromopyrrole mimetic for obtaining inhibitors of S. aureus and S. mutans biofilm formation. The most potent compd. in the series, 5-(trifluoromethoxy)indole-based analog 4b (MBIC50 = 20 μM), emerged as a promising hit for further optimization of novel inhibitors of S. aureus and S. mutans biofilms.
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    33. 33
      Tomašič, T.; Katsamakas, S.; Hodnik, Ž.; Ilaš, J.; Brvar, M.; Solmajer, T.; Montalvão, S.; Tammela, P.; Banjanac, M.; Ergović, G.; Anderluh, M.; Peterlin Mašič, L.; Kikelj, D. Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]Thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site. J. Med. Chem. 2015, 58, 5501– 5521,  DOI: 10.1021/acs.jmedchem.5b00489
      33
      Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site
      Tomasic, Tihomir; Katsamakas, Sotirios; Hodnik, Ziga; Ilas, Janez; Brvar, Matjaz; Solmajer, Tom; Montalvao, Sofia; Tammela, Paivi; Banjanac, Mihailo; Ergovic, Gabrijela; Anderluh, Marko; Masic, Lucija Peterlin; Kikelj, Danijel
      Journal of Medicinal Chemistry (2015), 58 (14), 5501-5521CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topol. state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogs, the authors identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologs. Some of the compds. possessed modest antibacterial activity against Gram pos. bacterial strains, while their evaluation against wild-type, impA and ΔtolCE. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochem. properties necessary for cell wall penetration. The study provides a rationale for optimization of this class of compds. toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
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    34. 34
      Gjorgjieva, M.; Tomašič, T.; Barančokova, M.; Katsamakas, S.; Ilaš, J.; Tammela, P.; Peterlin Mašič, L.; Kikelj, D. Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors. J. Med. Chem. 2016, 59, 8941– 8954,  DOI: 10.1021/acs.jmedchem.6b00864
      34
      Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors
      Gjorgjieva, Marina; Tomasic, Tihomir; Barancokova, Michaela; Katsamakas, Sotirios; Ilas, Janez; Tammela, Paivi; Peterlin Masic, Lucija; Kikelj, Danijel
      Journal of Medicinal Chemistry (2016), 59 (19), 8941-8954CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Bacterial DNA gyrase and topoisomerase IV control the topol. state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compd. 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV both from E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24, I) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compds. possessed weak antibacterial activity against Gram-pos. bacteria. These results provide a basis for structure-based optimization towards dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
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    35. 35
      Tomašič, T.; Mirt, M.; Barančoková, M.; Ilaš, J.; Zidar, N.; Tammela, P.; Kikelj, D. Design, Synthesis and Biological Evaluation of 4,5-Dibromo-N-(Thiazol-2-yl)-1H-Pyrrole-2-Carboxamide Derivatives as Novel DNA Gyrase Inhibitors. Bioorg. Med. Chem. 2017, 25, 338– 349,  DOI: 10.1016/j.bmc.2016.10.038
      35
      Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors
      Tomasic, Tihomir; Mirt, Matic; Barancokova, Michaela; Ilas, Janez; Zidar, Nace; Tammela, Paivi; Kikelj, Danijel
      Bioorganic & Medicinal Chemistry (2017), 25 (1), 338-349CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety was designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole-2,6-diamine derivs. inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 μM). Their "ring-opened" analogs, based on the 2-(2-aminothiazol-4-yl)acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 μM. Mol. docking expts. were conducted to study the binding modes of inhibitors.
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    36. 36
      Haroun, M.; Tratrat, C.; Kositzi, K.; Tsolaki, E.; Petrou, A.; Aldhubiab, B.; Attimarad, M.; Harsha, S.; Geronikaki, A.; Venugopala, K. N.; Elsewedy, H. S.; Sokovic, M.; Glamoclija, J.; Ciric, A. New Benzothiazole-Based Thiazolidinones as Potent Antimicrobial Agents. Design, Synthesis and Biological Evaluation. Curr. Top. Med. Chem. 2018, 18, 75– 87,  DOI: 10.2174/1568026618666180206101814
      36
      New Benzothiazole-based Thiazolidinones as Potent Antimicrobial Agents. Design, synthesis and Biological Evaluation
      Haroun, Michelyne; Tratrat, Christophe; Kositzi, Katerina; Tsolaki, Evangelia; Petrou, Anthi; Aldhubiab, Bandar; Attimarad, Mahesh; Harsha, Sree; Geronikaki, Athina; Venugopala, Katharigatta N.; Elsewedy, Heba S.; Sokovic, Marina; Glamoclija, Jasna; Ciric, Ana
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2018), 18 (1), 75-87CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      Thiazole and benzothiazole derivs., as well as thiazolidinones are very important scaffolds in medicinal chem. Literature has revealed that they possess a wide spectrum of biol. activities including antimicrobial activity. The goal of this paper is the designing of new benzothiazole based thiazolidinones and the evaluation of their biol. activities. The designed compds. were synthesized using classical org. synthesis methods. The antimicrobial activity was evaluated using the method of microdilution. The twelve newly synthesized compds. showed antimicrobial properties. All compds. appeared to be more active than ampicillin in most studied strains and in some cases, more active than streptomycin. Antifungal activity, in most cases was also better than the ref. drugs ketoconazole and bifonazole. The prediction of cytotoxicity revealed that the synthesized compds. were not toxic (LD50 350-1000 mg/kg of body wt.). Docking studies on the antibacterial activity confirmed the biol. results. The twelve new compds. were synthesized and studied for their antimicrobial activity. The compds. appeared to be promising antimicrobial agents and could be the lead compds. for new, more potent drugs. According to the docking prediction, the compds. could be MurB inhibitors.
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    37. 37
      Maddili, S. K.; Li, Z.-Z.; Kannekanti, V. K.; Bheemanaboina, R. R. Y.; Tuniki, B.; Tangadanchu, V. K. R.; Zhou, C.-H. Azoalkyl Ether Imidazo[2,1-b]Benzothiazoles as Potentially Antimicrobial Agents with Novel Structural Skeleton. Bioorg. Med. Chem. Lett. 2018, 28, 2426– 2431,  DOI: 10.1016/j.bmcl.2018.06.016
      37
      Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton
      Maddili, Swetha Kameswari; Li, Zhen-Zhen; Kannekanti, Vijaya Kumar; Bheemanaboina, Rammohan R. Yadav; Tuniki, Balaraju; Tangadanchu, Vijai Kumar Reddy; Zhou, Cheng-He
      Bioorganic & Medicinal Chemistry Letters (2018), 28 (14), 2426-2431CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good no. of the prepd. derivs. exhibited significant inhibitory properties against most of the tested strains. Esp. 2-methyl-5-nitroimidazole deriv. I presented superior inhibitory activity against MRSA and B. typhi with MIC = 4 μg/mL and MIC = 1 μg/mL, resp. The highly active compd. I showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. A mol. docking study exposed that the active mol. I could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chem. studies were also performed to explain the high antibacterial activity. Further investigation revealed that compd. I could significantly assoc. with gyrase-DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form I-DNA supramol. complex, which impart potent bioactivity.
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    38. 38
      Hameed, A.; Al-Rashida, M.; Uroos, M.; Abid Ali, S.; Khan, K. M. Schiff bases in medicinal chemistry: a patent review (2010–2015). Expert Opin. Ther. Pat. 2017, 27, 63– 79,  DOI: 10.1080/13543776.2017.1252752
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      Schiff bases in medicinal chemistry: a patent review (2010-2015)
      Hameed, Abdul; al-Rashida, Mariya; Uroos, Maliha; Ali, Syed Abid; Khan, Khalid Mohammed
      Expert Opinion on Therapeutic Patents (2017), 27 (1), 63-79CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
      A review. Schiff bases are synthetically accessible and structurally diverse compds., typically obtained by facile condensation between an aldehyde, or a ketone with primary amines. Schiff bases contain an azomethine (-C = N-) linkage that stitches together two or more biol. active arom./heterocyclic scaffolds to form various mol. hybrids with interesting biol. properties. Schiff bases are versatile metal complexing agents and have been known to coordinate all metals to form stable metal complexes with vast therapeutic applications. This review aims to provide a comprehensive overview of the various patented therapeutic applications of Schiff bases and their metal complexes from 2010 to 2015. Schiff bases are a popular class of compds. with interesting biol. properties. Schiff bases are also versatile metal complexing ligands and have been used to coordinate almost all d-block metals as well as lanthanides. Therapeutically, Schiff bases and their metal complexes have been reported to exhibit a wide range of biol. activities such as antibacterial including antimycobacterial, antifungal, antiviral, antimalarial, antiinflammatory, antioxidant, pesticidal, cytotoxic, enzyme inhibitory, and anticancer including DNA damage.
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    39. 39
      Nastasǎ, C.; Vodnar, D. C.; Ionuţ, I.; Stana, A.; Benedec, D.; Tamaian, R.; Oniga, O.; Tiperciuc, B. Antibacterial Evaluation and Virtual Screening of New Thiazolyl-Triazole Schiff Bases as Potential DNA-Gyrase Inhibitors. Int. J. Mol. Sci. 2018, 19, 222  DOI: 10.3390/ijms19010222
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      Antibacterial evaluation and virtual screening of new thiazolyl-triazole schiff bases as potential DNA-gyrase inhibitors
      Nastasa, Cristina; Vodnar, Dan C.; Ionut, Ioana; Anca Stana; Daniela Benedec; Tamaian, Radu; Oniga, Ovidiu; Tiperciuc, Brindusa
      International Journal of Molecular Sciences (2018), 19 (1), 222/1-222/18CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      The global spread of bacterial resistance to drugs used in therapy requires new potent and safe antimicrobial agents. DNA gyrases represent important targets in drug discovery. Schiff bases, thiazole, and triazole derivs. are considered key scaffolds in medicinal chem. Fifteen thiazolyl-triazole Schiff bases were evaluated for their antibacterial activity, measuring the growth inhibition zone diam., the min. inhibitory concn. (MIC), and the min. bactericidal concn. (MBC), against Gram-pos. (Staphylococcus aureus, Listeria monocytogenes) and Gram-neg. (Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa) bacteria. The inhibition of S. aureus and S. typhimurium was modest. Compds. B1, B2, and B9 showed a similar effect as ciprofloxacin, the antimicrobial ref., against L. monocytogenes. B10 displayed a better effect. Derivs. B1, B5#x2013;7, B9, and B11-15 expressed MIC values lower than the ref., against L. monocytogenes. B5, B6, and B11-15 strongly inhibited the growth of P. aeruginosa. All compds. were subjected to an in silico screening of the ADMET (absorption, distribution, metab., elimination, toxicity) properties. Mol. docking was performed on the gyrA and gyrB from L. monocytogenes. The virtual screening concluded that thiazolyl-triazole Schiff base B8 is the best drug-like candidate, satisfying requirements for both safety and efficacy, being more potent against the bacterial gyrA than ciprofloxacin.
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    40. 40
      Eakin, A. E.; Green, O.; Hales, N.; Walkup, G. K.; Bist, S.; Singh, A.; Mullen, G.; Bryant, J.; Embrey, K.; Gao, N.; Breeze, A.; Timms, D.; Andrews, B.; Uria-Nickelsen, M.; Demeritt, J.; Loch, J. T., 3rd; Hull, K.; Blodgett, A.; Illingworth, R. N.; Prince, B.; Boriack-Sjodin, P. A.; Hauck, S.; MacPherson, L. J.; Ni, H.; Sherer, B. Pyrrolamide DNA Gyrase Inhibitors: Fragment-Based Nuclear Magnetic Resonance Screening to Identify Antibacterial Agents. Antimicrob. Agents Chemother. 2012, 56, 1240– 1246,  DOI: 10.1128/AAC.05485-11
      40
      Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents
      Eakin, Ann E.; Green, Oluyinka; Hales, Neil; Walkup, Grant K.; Bist, Shanta; Singh, Alok; Mullen, George; Bryant, Joanna; Embrey, Kevin; Gao, Ning; Breeze, Alex; Timms, Dave; Andrews, Beth; Uria-Nickelsen, Maria; Demeritt, Julie; Loch, James T., III; Hull, Ken; Blodgett, April; Illingworth, Ruth N.; Prince, Bryan; Boriack-Sjodin, P. Ann; Hauck, Sheila; MacPherson, Lawrence J.; Ni, Haihong; Sherer, Brian
      Antimicrobial Agents and Chemotherapy (2012), 56 (3), 1240-1246CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compds. were identified by a fragment-based lead generation (FBLG) approach using NMR (NMR) screening to identify low-mol.-wt. compds. that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding const. of 1 mM formed the basis of the design and synthesis of a focused library of compds. that resulted in the rapid identification of a lead compd. that inhibited DNA gyrase with a 50% inhibitory concn. (IC50) of 3 μM. The potency of the lead compd. was further optimized by utilizing iterative X-ray crystallog. to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates contg. pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compds. was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clin. indications.
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    41. 41
      Sherer, B. A.; Hull, K.; Green, O.; Basarab, G.; Hauck, S.; Hill, P.; Loch, J. T.; Mullen, G.; Bist, S.; Bryant, J.; Boriack-Sjodin, A.; Read, J.; DeGrace, N.; Uria-Nickelsen, M.; Illingworth, R. N.; Eakin, A. E. Pyrrolamide DNA Gyrase Inhibitors: Optimization of Antibacterial Activity and Efficacy. Bioorg. Med. Chem. Lett. 2011, 21, 7416– 7420,  DOI: 10.1016/j.bmcl.2011.10.010
      41
      Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy
      Sherer, Brian A.; Hull, Kenneth; Green, Oluyinka; Basarab, Gregory; Hauck, Sheila; Hill, Pamela; Loch, James T., III; Mullen, George; Bist, Shanta; Bryant, Joanna; Boriack-Sjodin, Ann; Read, Jon; DeGrace, Nancy; Uria-Nickelsen, Maria; Illingworth, Ruth N.; Eakin, Ann E.
      Bioorganic & Medicinal Chemistry Letters (2011), 21 (24), 7416-7420CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochem. activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the mol. resulted in pyrrolamides with improved cellular activity and in vivo efficacy.
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    42. 42
      Basarab, G. S.; Hill, P. J.; Garner, C. E.; Hull, K.; Green, O.; Sherer, B. A.; Dangel, P. B.; Manchester, J. I.; Bist, S.; Hauck, S.; Zhou, F.; Uria-Nickelsen, M.; Illingworth, R. N.; Alm, R.; Rooney, M.; Eakin, A. E. Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099). J. Med. Chem. 2014, 57, 6060– 6082,  DOI: 10.1021/jm500462x
      42
      Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)
      Basarab, Gregory S.; Hill, Pamela J.; Garner, C. Edwin; Hull, Ken; Green, Oluyinka; Sherer, Brian A.; Dangel, P. Brian; Manchester, John I.; Bist, Shanta; Hauck, Sheila; Zhou, Fei; Uria-Nickelsen, Maria; Illingworth, Ruth; Alm, Richard; Rooney, Mike; Eakin, Ann E.
      Journal of Medicinal Chemistry (2014), 57 (14), 6060-6082CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      AZD5099 I is an antibacterial agent that entered phase 1 clin. trials targeting infections caused by Gram-pos. and fastidious Gram-neg. bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramol. hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compd. I showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency vs. the drug was low, and reports of clin. resistance due to alteration of the target are few. Hence, I could offer a novel treatment for serious issues of resistance to currently used antibacterials.
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    43. 43
      Yang, Y.; Severin, A.; Chopra, R.; Krishnamurthy, G.; Singh, G.; Hu, W.; Keeney, D.; Svenson, K.; Petersen, P. J.; Labthavikul, P.; Shlaes, D. M.; Rasmussen, B. A.; Failli, A. A.; Shumsky, J. S.; Kutterer, K. M.; Gilbert, A.; Mansour, T. S. 3,5-Dioxopyrazolidines, Novel Inhibitors of UDP-N- Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria. Antimicrob. Agents Chemother. 2006, 50, 556– 564,  DOI: 10.1128/AAC.50.2.556-564.2006
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      3,5-Dioxopyrazolidines, novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB) with activity against Gram-positive bacteria
      Yang, Youjun; Severin, Anatoly; Chopra, Rajiv; Krishnamurthy, Girija; Singh, Guy; Hu, William; Keeney, David; Svenson, Kristine; Petersen, Peter J.; Labthavikul, Pornpen; Shlaes, David M.; Rasmussen, Beth A.; Failli, Amedeo A.; Shumsky, Jay S.; Kutterer, Kristina M. K.; Gilbert, Adam; Mansour, Tarek S.
      Antimicrobial Agents and Chemotherapy (2006), 50 (2), 556-564CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
      A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compds. I, II, and III, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphylococcus aureus MurB, and E. coli MurA with 50% inhibitory concns. (IC50s) in the range of 4.1-6.8 μM, 4.3-10.3 μM, and 6.8-29.4 μM, resp. Compd. IV, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC50s, 24.5-35 μM). A fluorescence-binding assay indicated tight binding of III with E. coli MurB, giving a dissocn. const. of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with IV was obtained at 2.4 Å resoln. The crystal structure indicated the binding of a compd. at the active site of MurB and specific interactions with active-site residues and the bound FAD cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC50s of 0.39-11.1 μM. Antibacterial activity was obsd. for I-III (MICs, 0.25-16 μg/mL) and IV (MICs, 4-8 μg/mL) against gram-pos. bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
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    44. 44
      Bronson, J. J.; DenBleyker, K. L.; Falk, P. J.; Mate, R. A.; Ho, H.-T.; Pucci, M. J.; Snyder, L. B. Discovery of the First Antibacterial Small Molecule Inhibitors of MurB. Bioorg. Med. Chem. Lett. 2003, 13, 873– 875,  DOI: 10.1016/S0960-894X(02)01076-4
      44
      Discovery of the first antibacterial small molecule inhibitors of MurB
      Bronson, Joanne J.; DenBleyker, Kenneth L.; Falk, Paul J.; Mate, Robert A.; Ho, Hsu-Tso; Pucci, Michael J.; Snyder, Lawrence B.
      Bioorganic & Medicinal Chemistry Letters (2003), 13 (5), 873-875CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
      A series of imidazolinone analogs was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity. Analogs of a known MurB enzyme inhibitor, 5-[2-[[2-(2-chlorophenyl)ethyl]amino]-2-oxoethyl]-α-butyl-2-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-4-oxo-(αS)-3-thiazolidineacetic acid, were prepd. and evaluated as antibacterial agents. Analogs included derivs. of α-butyl-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid Me ester and α-butyl-3-[2-[[2-(2-chlorophenyl)ethyl]amino]-2-oxoethyl]-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid and α-butyl-3-[2-[[(3,4-dichlorophenyl)methyl]amino]-2-oxoethyl]-2,3-dihydro-5-[3-[4-(1,1-dimethylethyl)phenoxy]phenyl]-2-oxo-(αS)-1H-imidazole-1-acetic acid. MurB has no known counterpart in eukaryotes.
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    45. 45
      Liaras, K.; Fesatidou, M.; Geronikaki, A. Thiazoles and Thiazolidinones as COX/LOX Inhibitors. Molecules 2018, 23, 685,  DOI: 10.3390/molecules23030685
      45
      Thiazoles and thiazolidinones as COX/LOX inhibitors
      Liaras, Konstantinos; Fesatidou, Maria; Geronikaki, Athina
      Molecules (2018), 23 (3), 685/1-685/21CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the prodn. of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a no. of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biol. active compds. of natural origin, as well as synthetic mols. that possess a wide range of pharmacol. activities. This review focuses on the biol. activity of several thiazole and thiazolidinone derivs. as COX-1/COX-2 and LOX inhibitors.
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    46. 46
      Pattan, S. R.; Kekare, P.; Patil, A.; Nikalje, A.; Kittur, B. S. Studies on the Synthesis of Novel 2,4-Thiazolidinedione Derivatives with Antidiabetic Activity. Iran. J. Pharm. Sci. 2009, 5, 225– 230
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      Studies on the synthesis of novel 2,4-thiazolidinedione derivatives with antidiabetic activity
      Pattan, Shashikant R.; Kekare, Prajact; Patil, Ashwini; Nikalje, Ana; Kittur, B. S.
      Iranian Journal of Pharmaceutical Sciences (2009), 5 (4), 225-230CODEN: IJPSUU; ISSN:1735-2444. (Shiraz University of Medical Sciences, Faculty of Pharmacy)
      A new series of thiazolidinediones was synthesized. The structures of these compds. were established by IR, 1H NMR, and elemental anal. All of the compds. were screened for antidiabetic activity on albino rats. Most of the compds. showed significant antidiabetic activity when compared with the std. glibenclamide.
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    47. 47
      Suryawanshi, R.; Jadhav, S.; Makwana, N.; Desai, D.; Chaturbhuj, D.; Sonawani, A.; Idicula-Thomas, S.; Murugesan, V.; Katti, S. B.; Tripathy, S.; Paranjape, R.; Kulkarni, S. Evaluation of 4-Thiazolidinone Derivatives as Potential Reverse Transcriptase Inhibitors against HIV-1 Drug Resistant Strains. Bioorg. Chem. 2017, 71, 211– 218,  DOI: 10.1016/j.bioorg.2017.02.007
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      Evaluation of 4-thiazolidinone derivatives as potential reverse transcriptase inhibitors against HIV-1 drug resistant strains
      Suryawanshi, Rahul; Jadhav, Sushama; Makwana, Nandini; Desai, Dipen; Chaturbhuj, Devidas; Sonawani, Archana; Idicula-Thomas, Susan; Murugesan, Vanangamudi; Katti, Seturam B.; Tripathy, Srikanth; Paranjape, Ramesh; Kulkarni, Smita
      Bioorganic Chemistry (2017), 71 (), 211-218CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
      Rapid emergence of drug resistance is crucial in management of HIV infection limiting implementation of efficacious drugs in the ART regimen. Designing new mols. against HIV drug resistant strains is utmost essential. Based on the anti-HIV-1 activity, we selected four 4-thiazolidinone derivs. (S009-1908, S009-1909, S009-1911, S009-1912) and studied their interaction with reverse transcriptase (RT) from a panel of 10 clin. isolates (8 nevirapine resistant and two susceptible) using in silico methods, and inhibition pattern using in vitro cell based assays. On the basis of binding affinity obsd. in in silico anal., 2-(2-chloro-6-nitrophenyl)-3-(4, 6-dimethylpyridin-2-yl) thiazolidin-4-one (S009-1912) was identified as the lead mol. followed by S009-1908, S009-1909 and S009-1911. The in vitro activity against the same panel was assessed using TZM-bl assay (IC50: 0.4-11.44 μg/mL, TI: 4-126) and subsequently in PBMC assay against a nevirapine resistant clin. isolate (IC50: 0.8-6.65 μg/mL, TI: 8.31-11.43) and std. strain from NIH ARRRP (IC50: 0.95-3.6 μg/mL, TI: 9-26). The study shows analog with pyrimidin-2-yl amino substitution at N-3 position of thiazolidin-4-one ring (S009-1908, S009-1909, S009-1911) exhibited enhanced activity as compared to pyridin-2-yl substituted derivs. (S009-1912), suggesting the use 4-thiazolidinones for developing potent inhibitors against HIV-1 drug resistant strains.
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    48. 48
      Kesicki, E. A.; Bailey, M. A.; Ovechkina, Y.; Early, J. V.; Alling, T.; Bowman, J.; Zuniga, E. S.; Dalai, S.; Kumar, N.; Masquelin, T.; Hipskind, P. A.; Odingo, J. O.; Parish, T. Synthesis and Evaluation of the 2-Aminothiazoles as Anti-Tubercular Agents. PLoS One 2016, 11, e0155209  DOI: 10.1371/journal.pone.0155209
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      Synthesis and evaluation of the 2-aminothiazoles as anti-tubercular agents
      Kesicki, Edward A.; Bailey, Mai A.; Ovechkina, Yulia; Early, Julie V.; Alling, Torey; Bowman, Julie; Zuniga, Edison S.; Dalai, Suryakanta; Kumar, Naresh; Masquelin, Thierry; Hipskind, Philip A.; Odingo, Joshua O.; Parish, Tanya
      PLoS One (2016), 11 (5), e0155209/1-e0155209/25CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large no. of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We detd. that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar min. inhibitory concns. being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel antitubercular agents.
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    49. 49
      Marques, G. H.; Kunzler, A.; Bareño, V. D. O.; Drawanz, B. B.; Mastelloto, H. G.; Leite, F. R. M.; Nascimento, G. G.; Nascente, P. S.; Siqueira, G. M.; Cunico, W. Antifungal Activity of 3-(Heteroaryl-2-yl-methyl)Thiazolidinone Derivatives. Med. Chem. 2014, 10, 355– 360,  DOI: 10.2174/15734064113099990030
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      Antifungal Activity of 3-(heteroaryl-2-ylmethyl)thiazolidinone Derivatives
      Marques, Gabriela H.; Kunzler, Alice; Bareno, Valeria D. O.; Drawanz, Bruna B.; Mastelloto, Hellen G.; Leite, Fabio R. M.; Nascimento, Gustavo G.; Nascente, Patricia S.; Siqueira, Geonir M.; Cunico, Wilson
      Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 10 (4), 355-360CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
      Thiazolidinones, synthesized from multicomponent reactions of 2-heteroarylmethylamine, arenealdehydes and mercaptoacetic acid, have been tested against six yeasts, namely Candida albicans, C. parapsilosis, C. guilliermondii, Cryptococcus laurentii, Trichosporon asahii and Rhodotorula spp. The activities were expressed as min. inhibitory concns. (MIC) and the min. fungicidal concns. (MFC). The most affected yeasts were Rhodotorula spp. and T. asahii. The cytotoxicities of the thiazolidinones against the fibroblast 3T3/NIH cell line are also described. The antifungal results and the low cytotoxicity of the compds. in this work provide good guides for the further development of active compds.
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    50. 50
      Gupta, A.; Singh, R.; Sonar, P. K.; Saraf, S. K. Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation. Biochem. Res. Int. 2016, 2016 (216), 8086762,  DOI: 10.1155/2016/8086762
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      Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation
      Gupta Amit; Singh Rajendra; Sonar Pankaj K; Saraf Shailendra K
      Biochemistry research international (2016), 2016 (), 8086762 ISSN:2090-2247.
      A series of new 4-thiazolidinone derivatives was synthesized, characterized by spectral techniques, and screened for antimicrobial activity. All the compounds were evaluated against five Gram-positive bacteria, two Gram-negative bacteria, and two fungi, at concentrations of 50, 100, 200, 400, 800, and 1600 μg/mL, respectively. Minimum inhibitory concentrations of all the compounds were also determined and were found to be in the range of 100-400 μg/mL. All the compounds showed moderate-to-good antimicrobial activity. Compounds 4a [2-(4-fluoro-phenyl)-3-(4-methyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-thiazolidin-4-one] and 4e [3-(4,6-dimethyl-pyrimidin-2-yl)-2-(2-methoxy-phenyl)-thiazolidin-4-one] were the most potent compounds of the series, exhibiting marked antimicrobial activity against Pseudomonas fluorescens, Staphylococcus aureus, and the fungal strains. Thus, on the basis of results obtained, it may be concluded that synthesized compounds exhibit a broad spectrum of antimicrobial activity.
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    51. 51
      Andres, C. J.; Bronson, J. J.; D’Andrea, S. V.; Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.; Harte, W. E.; Ho, H.-T.; Misco, P. F.; Robertson, J. G.; Stock, D.; Sun, Y.; Walsh, A. W. 4-Thiazolidinones: Novel Inhibitors of the Bacterial Enzyme MurB. Bioorg. Med. Chem. Lett. 2000, 10, 715– 717,  DOI: 10.1016/S0960-894X(00)00073-1
      51
      4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB
      Andres, Charles J.; Bronson, Joanne J.; D'Andrea, Stanley V.; Deshpande, Milind S.; Falk, Paul J.; Grant-Young, Katharine A.; Harte, William E.; Ho, Hsu-Tso; Misco, Peter F.; Robertson, James G.; Stock, David; Sun, Yaxiong; Walsh, Ann W.
      Bioorganic & Medicinal Chemistry Letters (2000), 10 (8), 715-717CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)
      4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the enzyme in vitro. This activity, coupled with the design principles of the thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biol. selector.
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    52. 52
      Patel, H.; Mishra, L.; Noolvi, M.; Karpoormath, R.; Singh Cameotra, S. Synthesis, in Vitro Evaluation, and Molecular Docking Studies of Azetidinones and Thiazolidinones of 2-Amino-5-Cyclopropyl-1,3,4-Thiadiazole as Antibacterial Agents. Arch. Pharm. 2014, 347, 668– 684,  DOI: 10.1002/ardp.201400140
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      Synthesis, in vitro evaluation, and molecular docking studies of azetidinones and thiazolidinones of 2-amino-5-cyclopropyl-1,3,4-thiadiazole as antibacterial agents
      Patel, Harun; Mishra, Lishu; Noolvi, Malleshappa; Karpoormath, Rajshekhar; Singh Cameotra, Swaranjit
      Archiv der Pharmazie (Weinheim, Germany) (2014), 347 (9), 668-684CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In an attempt to find a new class of antimicrobial agents, a series of novel azetidin-2-ones 3a-e and thiazolidin-4-ones 4a-e of 2-amino-5-cyclopropyl-1,3,4-thiadiazole were synthesized. The synthesized compds. were confirmed by m.p., IR, 1H NMR, 13C NMR, and mass spectroscopy. The β-lactam deriv. (3e) was found to be the most potent compd. of the series displaying excellent antibacterial activities against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa with MIC values of 15.60, 31.50, 62.50, and 125 μg/mL, resp., as compared to the pos. control drug ampicillin. Mol. docking studies and detn. of the leakage of UV260- and UV280-absorbing material (nucleic acid material and protein) confirmed that the synthesized compds. inhibit cell wall synthesis by inhibiting PTB (transpeptidase enzyme). Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use, thereby indicating their potential as a drug-like mols.
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    53. 53
      Ito, A.; Nishikawa, T.; Matsumoto, S.; Yoshizawa, H.; Sato, T.; Nakamura, R.; Tsuji, M.; Yamano, Y. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2016, 60, 7396– 7401,  DOI: 10.1128/AAC.01405-16
      53
      Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa
      Ito, Akinobu; Nishikawa, Toru; Matsumoto, Shuhei; Yoshizawa, Hidenori; Sato, Takafumi; Nakamura, Rio; Tsuji, Masakatsu; Yamano, Yoshinori
      Antimicrobial Agents and Chemotherapy (2016), 60 (12), 7396-7401CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the 3rd-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not obsd. when 1 of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.
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    54. 54
      Zhanel, G. G.; Golden, A. R.; Zelenitsky, S.; Wiebe, K.; Lawrence, C. K.; Adam, H. J.; Idowu, T.; Domalaon, R.; Schweizer, F.; Zhanel, M. A.; Lagacé-Wiens, P. R. S.; Walkty, A. J.; Noreddin, A.; Lynch, J. P., III; Karlowsky, J. A. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 2019, 79, 271– 289,  DOI: 10.1007/s40265-019-1055-2
      54
      Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli
      Zhanel, George G.; Golden, Alyssa R.; Zelenitsky, Sheryl; Wiebe, Karyn; Lawrence, Courtney K.; Adam, Heather J.; Idowu, Temilolu; Domalaon, Ronald; Schweizer, Frank; Zhanel, Michael A.; Lagace-Wiens, Philippe R. S.; Walkty, Andrew J.; Noreddin, Ayman; Lynch III, Joseph P.; Karlowsky, James A.
      Drugs (2019), 79 (3), 271-289CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
      A review. Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. The primary outcome measure was a composite of clin. cure and microbiol. eradication at the test-of-cure visit, i.e., 7 days after the end of treatment in the microbiol. intent-to-treat population. Secondary outcome measures included microbiol. response per pathogen and per patient at early assessment, end of treatment, TOC, and follow-up; clin. response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concns. of cefiderocol; and the no. of participants with adverse events. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-neg. pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-assocd. pneumonia or healthcare-assocd. pneumonia caused by Gram-neg. pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.
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    55. 55
      Han, S.; Zaniewski, R. P.; Marr, E. S.; Lacey, B. M.; Tomaras, A. P.; Evdokimov, A.; Miller, J. R.; Shanmugasundaram, V. Structural Basis for Effectiveness of Siderophore-Conjugated Monocarbams against Clinically Relevant Strains of Pseudomonas Aeruginosa. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 22002– 22007,  DOI: 10.1073/pnas.1013092107
      55
      Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa
      Han, Seungil; Zaniewski, Richard P.; Marr, Eric S.; Lacey, Brian M.; Tomaras, Andrew P.; Evdokimov, Artem; Miller, J. Richard; Shanmugasundaram, Veerabahu
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (51), 22002-22007, S22002/1-S22002/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Pseudomonas aeruginosa is an opportunistic Gram-neg. pathogen that causes nosocomial infections for which there are limited treatment options. Penicillin-binding protein PBP3, a key therapeutic target, is an essential enzyme responsible for the final steps of peptidoglycan synthesis and is covalently inactivated by β-lactam antibiotics. Here we disclose the first high resoln. cocrystal structures of the P. aeruginosa PBP3 with both novel and marketed β-lactams. These structures reveal a conformational rearrangement of Tyr532 and Phe533 and a ligand-induced conformational change of Tyr409 and Arg489. The well-known affinity of the monobactam aztreonam for P. aeruginosa PBP3 is due to a distinct hydrophobic arom. wall composed of Tyr503, Tyr532, and Phe533 interacting with the gem-di-Me group. The structure of MC-1, a new siderophore-conjugated monocarbam complexed with PBP3 provides mol. insights for lead optimization. Importantly, we have identified a novel conformation that is distinct to the high-mol.-wt. class B PBP subfamily, which is identifiable by common features such as a hydrophobic arom. wall formed by Tyr503, Tyr532, and Phe533 and the structural flexibility of Tyr409 flanked by two glycine residues. This is also the first example of a siderophore-conjugated triazolone-linked monocarbam complexed with any PBP. Energetic anal. of tightly and loosely held computed hydration sites indicates protein desolvation effects contribute significantly to PBP3 binding, and anal. of hydration site energies allows rank ordering of the second-order acylation rate consts. Taken together, these structural, biochem., and computational studies provide a mol. basis for recognition of P. aeruginosa PBP3 and open avenues for future design of inhibitors of this class of PBPs.
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    56. 56
      Sauvage, E.; Terrak, M. Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials. Antibiotics 2016, 5, 12,  DOI: 10.3390/antibiotics5010012
      56
      Glycosyltransferases and transpeptidases/penicillin-binding proteins: valuable targets for new antibacterials
      Sauvage, Eric; Terrak, Mohammed
      Antibiotics (Basel, Switzerland) (2016), 5 (1), 12/1-12/27CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
      Peptidoglycan (PG) is an essential macromol. sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clin. useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by β-lactam derivs., but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addn. to traditional β-lactams, other classes of mols. (non-β-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes.
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    57. 57
      Dunn, G. L. Ceftizoxime and Other Third-Generation Cephalosporins: Structure-Activity Relationships. J. Antimicrob. Chemother. 1982, 10, 1– 10,  DOI: 10.1093/jac/10.suppl_C.1
      57
      Ceftizoxime and other third-generation cephalosporins: structure-activity relationships
      Dunn, G. L.
      Journal of Antimicrobial Chemotherapy (1982), 10 (Suppl. C), 1-10CODEN: JACHDX; ISSN:0305-7453.
      A review with 23 refs. on structure-activity relations of ceftizoxime (I) [68401-81-0] and other aminothiazolyloximino analogs of cephalosporin antibiotics.
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    58. 58
      Kohira, N.; West, J.; Ito, A.; Ito-Horiyama, T.; Nakamura, R.; Sato, T.; Rittenhouse, S.; Tsuji, M.; Yamano, Y. In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains. Antimicrob. Agents Chemother. 2016, 60, 729– 734,  DOI: 10.1128/AAC.01695-15
      58
      In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains
      Kohira, Naoki; West, Joshua; Ito, Akinobu; Ito-Horiyama, Tsukasa; Nakamura, Rio; Sato, Takafumi; Rittenhouse, Stephen; Tsuji, Masakatsu; Yamano, Yoshinori
      Antimicrobial Agents and Chemotherapy (2016), 60 (2), 729-734CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clin. isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the 1st set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all ≤1 μg/mL, and there were only 8 isolates (1.3%) among these 617 clin. isolates with MIC values of ≥8 μg/mL. In the 2nd set, the MIC values of S-649266 were ≤4 μg/mL against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addn., S-649266 showed MIC values of ≤2 μg/mL against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/mL are uncertain. This is the 1st report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.
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    59. 59
      Portsmouth, S.; van Veenhuyzen, D.; Echols, R.; Machida, M.; Ferreira, J. C. A.; Ariyasu, M.; Tenke, P.; Nagata, T. D. Cefiderocol versus Imipenem-Cilastatin for the Treatment of Complicated Urinary Tract Infections Caused by Gram-Negative Uropathogens: A Phase 2, Randomised, Double-Blind, Non-Inferiority Trial. Lancet Infect. Dis. 2018, 18, 1319– 1328,  DOI: 10.1016/S1473-3099(18)30554-1
      59
      Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial
      Portsmouth, Simon; van Veenhuyzen, David; Echols, Roger; Machida, Mitsuaki; Ferreira, Juan Camilo Arjona; Ariyasu, Mari; Tenke, Peter; Nagata, Tsutae Den
      Lancet Infectious Diseases (2018), 18 (12), 1319-1328CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)
      We assessed efficacy and safety of cefiderocol vs. imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-neg. infections. Adults (≥18 years) admitted to hospital with a clin. diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h i.v. infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7-14 days. Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). I.v. infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-neg. infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration.
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    60. 60
      Zhang, G.; Meredith, T. C.; Kahne, D. On the Essentiality of Lipopolysaccharide to Gram-Negative Bacteria. Curr. Opin. Microbiol. 2013, 16, 779– 785,  DOI: 10.1016/j.mib.2013.09.007
      60
      On the essentiality of lipopolysaccharide to Gram-negative bacteria
      Zhang, Ge; Meredith, Timothy C.; Kahne, Daniel
      Current Opinion in Microbiology (2013), 16 (6), 779-785CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
      A review. Lipopolysaccharide is a highly acylated saccharolipid located on the outer leaflet of the outer membrane of Gram-neg. bacteria. Lipopolysaccharide is crit. to maintaining the barrier function preventing the passive diffusion of hydrophobic solutes such as antibiotics and detergents into the cell. Lipopolysaccharide has been considered an essential component for outer membrane biogenesis and cell viability based on pioneering studies in the model Gram-neg. organisms Escherichia coli and Salmonella. With the isolation of lipopolysaccharide-null mutants in Neisseria meningitidis, Moraxella catarrhalis, and most recently in Acinetobacter baumannii, it has become increasingly apparent that lipopolysaccharide is not an essential outer membrane building block in all organisms. We suggest the accumulation of toxic intermediates, misassembly of essential outer membrane porins, and outer membrane stress response pathways that are activated by mislocalized lipopolysaccharide may collectively contribute to the obsd. strain-dependent essentiality of lipopolysaccharide.
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    61. 61
      Kneidinger, B.; Marolda, C.; Graninger, M.; Zamyatina, A.; McArthur, F.; Kosma, P.; Valvano, M. A.; Messner, P. Biosynthesis Pathway of ADP-L-Glycero-Beta-D-Manno-Heptose in Escherichia Coli. J. Bacteriol. 2002, 184, 363– 369,  DOI: 10.1128/JB.184.2.363-369.2002
      61
      Biosynthesis pathway of ADP-L-glycero-β-D-manno-heptose in Escherichia coli
      Kneidinger, Bernd; Marolda, Cristina; Graninger, Michael; Zamyatina, Alla; McArthur, Fiona; Kosma, Paul; Valvano, Miguel A.; Messner, Paul
      Journal of Bacteriology (2002), 184 (2), 363-369CODEN: JOBAAY; ISSN:0021-9193. (American Society for Microbiology)
      The steps involved in the biosynthesis of the ADP-L-glycero-β-D-manno-heptose (ADP-L-β-D-heptose) precursor of the inner core lipopolysaccharide (LPS) have not been completely elucidated. In this work, we have purified the enzymes involved in catalyzing the intermediate steps leading to the synthesis of ADP-D-β-D-heptose and have biochem. characterized the reaction products by high-performance anion-exchange chromatog. We have also constructed a deletion in a novel gene, gmhB (formerly yaeD), which results in the formation of an altered LPS core. This mutation confirms that the GmhB protein is required for the formation of ADP-D-β-D-heptose. Our results demonstrate that the synthesis of ADP-D-β-D-heptose in Escherichia coli requires three proteins, GmhA (sedoheptulose 7-phosphate isomerase), HldE (bifunctional D-β-D-heptose 7-phosphate kinase/D-β-D-heptose 1-phosphate adenylyltransferase), and GmhB (D,D-heptose 1,7-bisphosphate phosphatase), as well as ATP and the ketose phosphate precursor sedoheptulose 7-phosphate. A previously characterized epimerase, formerly named WaaD (RfaD) and now renamed HldD, completes the pathway to form the ADP-L-β-D-heptose precursor utilized in the assembly of inner core LPS.
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    62. 62
      Desroy, N.; Moreau, F.; Briet, S.; Le Fralliec, G.; Floquet, S.; Durant, L.; Vongsouthi, V.; Gerusz, V.; Denis, A.; Escaich, S. Towards Gram-Negative Antivirulence Drugs: New Inhibitors of HldE Kinase. Bioorg. Med. Chem. 2009, 17, 1276– 1289,  DOI: 10.1016/j.bmc.2008.12.021
      62
      Towards Gram-negative antivirulence drugs: New inhibitors of HldE kinase
      Desroy, Nicolas; Moreau, Francois; Briet, Sophia; LeFralliec, Geraldine; Floquet, Stephanie; Durant, Lionel; Vongsouthi, Vanida; Gerusz, Vincent; Denis, Alexis; Escaich, Sonia
      Bioorganic & Medicinal Chemistry (2009), 17 (3), 1276-1289CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Gram-neg. bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochem. assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure-activity relation of this series of inhibitors led to highly potent compds.
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    63. 63
      De Leon, G. P.; Elowe, N. H.; Koteva, K. P.; Valvano, M. A.; Wright, G. D. An in Vitro Screen of Bacterial Lipopolysaccharide Biosynthetic Enzymes Identifies an Inhibitor of ADP-Heptose Biosynthesis. Chem. Biol. 2006, 13, 437– 441,  DOI: 10.1016/j.chembiol.2006.02.010
      63
      An In Vitro Screen of Bacterial Lipopolysaccharide Biosynthetic Enzymes Identifies an Inhibitor of ADP-Heptose Biosynthesis
      De Leon, Gladys P.; Elowe, Nadine H.; Koteva, Kalinka P.; Valvano, Miguel A.; Wright, Gerard D.
      Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (4), 437-441CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
      The lipopolysaccharide (LPS)-rich outer membrane of gram-neg. bacteria provides a protective barrier that insulates these organisms from the action of numerous antibiotics. Breach of the LPS layer can therefore provide access to the cell interior to otherwise impermeant toxic mols. and can expose vulnerable binding sites for immune system components such as complement. Inhibition of LPS biosynthesis, leading to a truncated LPS mol., is an alternative strategy for antibacterial drug development in which this vital cellular structure is weakened. A significant challenge for in vitro screens of small mols. for inhibition of LPS biosynthesis is the difficulty in accessing the complex carbohydrate substrates. We have optimized an assay of the enzymes required for LPS heptose biosynthesis that simultaneously surveys five enzyme activities by using com. available substrates and report its use in a small-mol. screen that identifies an inhibitor of heptose synthesis.
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    64. 64
      Caroff, M.; Karibian, D. Structure of Bacterial Lipopolysaccharides. Carbohydr. Res. 2003, 338, 2431– 2447,  DOI: 10.1016/j.carres.2003.07.010
      64
      Structure of bacterial lipopolysaccharides
      Caroff, Martine; Karibian, Doris
      Carbohydrate Research (2003), 338 (23), 2431-2447CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)
      A review. Bacterial lipopolysaccharides are the major components of the outer surface of Gram-neg. bacteria. They are often of interest in medicine for their immunomodulatory properties. In small amts. they can be beneficial, but in larger amts. they may cause endotoxic shock. Although they share a common architecture, their structural details exert a strong influence on their activity. These mols. comprise: a lipid moiety, called lipid A, which is considered to be the endotoxic component, a glycosidic part consisting of a core of approx. 10 monosaccharides and, in "smooth-type" lipopolysaccharides, a third region, named O-chain, consisting of repetitive subunits of one to eight monosaccharides responsible for much of the immunospecificity of the bacterial cell.
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    65. 65
      Singh, M.; Kumar Singh, S.; Gangwar, M.; Sellamuthu, S.; Nath, G.; Singh, S. K. Design, Synthesis and Mode of Action of Some New 2-(4’-Aminophenyl) Benzothiazole Derivatives as Potent Antimicrobial Agents. Lett. Drug Design Discovery 2016, 13, 429– 437,  DOI: 10.2174/1570180812666150821003220
      65
      Design, Synthesis and Mode of Action of Some New 2-(4'-aminophenyl) benzothiazole Derivatives as Potent Antimicrobial Agents
      Singh, Meenakshi; Singh, Sudhir Kumar; Gangwar, Mayank; Sellamuthu, Satheeshkumar; Nath, Gopal; Singh, Sushil K.
      Letters in Drug Design & Discovery (2016), 13 (5), 429-437CODEN: LDDDAW; ISSN:1875-628X. (Bentham Science Publishers Ltd.)
      The rapid evolution of antibiotic resistance poses a serious threat to public health. The development of heterocyclic benzothiazole derivs., as efficient and potential agents, has been the focus of antibacterial drug discovery. Present study attempts to evaluate the antibacterial activity and mechanism of action of novel 2-(4'- aminophenyl) benzothiazole derivs. Methods: Antibacterial activity of novel benzothiazole derivs. was evaluated by agar disk diffusion method against a panel of susceptible Gram-pos. and Gram-neg. strains. The mechanism of action was explored by bactericidal kinetics, membrane depolarization, fluorescent assisted cell cytometry and DNA cleavage studies. Results: the authors' findings revealed that compds. A07a and A07b turned out to be the most potent analogs having min. inhibitory concn. values in the range of 3.91-31.2 μg/mL against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli. The new benzothiazole derivs. displayed different modes of action as elucidated by the studies on intact bacterial cells and plasmid DNA. The structure activity relationship studies showed prominent activity of compd. A07a contg. oxime moiety on carbonyl carbon along with less bulky electron releasing and lipophillic group (methoxy and chloro) in Ph ring at C2 position of 2-(4'-aminophenyl) benzothiazole ring system. Conclusion: The potent antibacterial activity of compds. (A07a and A07b) was mediated by membrane perturbing and intracellular mode of actions. These results further validate the use of these derivs. in the treatment of microbial diseases and provide scope for further research.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFCrsb8%253D&md5=96350392fc642e8904f0bccc35f40ea6
    66. 66
      Rajendran, V.; Kalita, P.; Shukla, H.; Kumar, A.; Tripathi, T. Aminoacyl-TRNA Synthetases: Structure, Function, and Drug Discovery. Int. J. Biol. Macromol. 2018, 111, 400– 414,  DOI: 10.1016/j.ijbiomac.2017.12.157
      66
      Aminoacyl-tRNA synthetases: Structure, function, and drug discovery
      Rajendran, Vijayakumar; Kalita, Parismita; Shukla, Harish; Kumar, Awanish; Tripathi, Timir
      International Journal of Biological Macromolecules (2018), 111 (), 400-414CODEN: IJBMDR; ISSN:0141-8130. (Elsevier B.V.)
      Aminoacyl-tRNA synthetases (AARSs) are the enzymes that catalyze the aminoacylation reaction by covalently linking an amino acid to its cognate tRNA in the first step of protein translation. Beyond this classical function, these enzymes are also known to have a role in several metabolic and signaling pathways that are important for cell viability. Study of these enzymes is of great interest to the researchers due to its pivotal role in the growth and survival of an organism. Further, unfolding the interesting structural and functional aspects of these enzymes in the last few years has qualified them as a potential drug target against various diseases. Here we review the classification, function, and the conserved as well the appended structural architecture of these enzymes in detail, including its assocn. with multi-synthetase complexes. We also considered their role in human diseases in terms of mutations and autoantibodies against AARSs. Finally, we have discussed the available inhibitors against AARSs. This review offers comprehensive information on AARSs under a single canopy that would be a good inventory for researchers working in this area.
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    67. 67
      Giegé, R.; Springer, M. Aminoacyl-TRNA Synthetases in the Bacterial World. EcoSal Plus 2016, 7, ESP-0002-2016,  DOI: 10.1128/ecosalplus.ESP-0002-2016
      There is no corresponding record for this reference.
    68. 68
      Stana, A.; Vodnar, D. C.; Marc, G.; Benedec, D.; Tiperciuc, B.; Tamaian, R.; Oniga, O. Antioxidant Activity and Antibacterial Evaluation of New Thiazolin-4-One Derivatives as Potential Tryptophanyl-TRNA Synthetase Inhibitors. J. Enzyme Inhib. Med. Chem. 2019, 34, 898– 908,  DOI: 10.1080/14756366.2019.1596086
      68
      Antioxidant activity and antibacterial evaluation of new thiazolin-4-one derivatives as potential tryptophanyl-tRNA synthetase inhibitors
      Stana, Anca; Vodnar, Dan C.; Marc, Gabriel; Benedec, Daniela; Tiperciuc, Brindusa; Tamaian, Radu; Oniga, Ovidiu
      Journal of Enzyme Inhibition and Medicinal Chemistry (2019), 34 (1), 898-908CODEN: JEIMAZ; ISSN:1475-6366. (Taylor & Francis Ltd.)
      The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivs. were evaluated for their antibacterial activity by detg. the growth inhibition zone diam., the min. inhibitory concn. (MIC), and the min. bactericidal concn. (MBC), against gram-pos. and gram-neg. bacteria. Compds. , , and expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compds. and displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compds. were subjected to mol. docking on tryptophanyl-tRNA synthetase. Compds. , , and exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compds. was evaluated by four spectrophotometric methods. Thiazolin-4-ones , and presented better antiradical activity than ascorbic acid, trolox and BHT, used as refs.
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    69. 69
      Cascioferro, S.; Totsika, M.; Schillaci, D. Sortase A: An Ideal Target for Anti-Virulence Drug Development. Microb. Pathog. 2014, 77C, 105– 112,  DOI: 10.1016/j.micpath.2014.10.007
      There is no corresponding record for this reference.
    70. 70
      Oniga, S. D.; Araniciu, C.; Palage, M. D.; Popa, M.; Chifiriuc, M.-C.; Marc, G.; Pirnau, A.; Stoica, C. I.; Lagoudis, I.; Dragoumis, T.; Oniga, O. New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Molecules 2017, 22, 1827,  DOI: 10.3390/molecules22111827
      70
      New 2-phenylthiazoles as potential sortase a inhibitors: synthesis, biological evaluation and molecular docking
      Oniga, Smaranda Dafina; Araniciu, Catalin; Palage, Mariana Doina; Popa, Marcela; Chifiriuc, Mariana Carmen; Marc, Gabriel; Pirnau, Adrian; Stoica, Cristina Ioana; Lagoudis, Ioannis; Dragoumis, Theodoros; Oniga, Ovidiu
      Molecules (2017), 22 (11), 1827/1-1827/18CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-anal. of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochem. characterization confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compds. have a reduced activity against bacterial cell viability. However, the compds. prevent biofilm formation at very low concns., esp. in the case of E. faecalis. Mol. docking studies performed est. that this is most likely due to the inhibition of Sortase A. The new compds. could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.
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    71. 71
      Parrino, B.; Diana, P.; Cirrincione, G.; Cascioferro, S. Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy. Open Med. Chem. J. 2018, 12, 84– 87,  DOI: 10.2174/1874104501812010084
      71
      Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy
      Parrino Barbara; Diana Patrizia; Cirrincione Girolamo; Cascioferro Stella
      The open medicinal chemistry journal (2018), 12 (), 84-87 ISSN:1874-1045.
      There is no expanded citation for this reference.
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    72. 72
      Li, X.-H.; Lee, J.-H. Antibiofilm Agents: A New Perspective for Antimicrobial Strategy. J. Microbiol. 2017, 55, 753– 766,  DOI: 10.1007/s12275-017-7274-x
      72
      Antibiofilm agents: A new perspective for antimicrobial strategy
      Li, Xi-Hui; Lee, Joon-Hee
      Journal of Microbiology (Seoul, Republic of Korea) (2017), 55 (10), 753-766CODEN: JOMIFG; ISSN:1225-8873. (Microbiological Society of Korea)
      Biofilms are complex microbial architectures that attach to surfaces and encase microorganisms in a matrix composed of self-produced hydrated extracellular polymeric substances (EPSs). In biofilms, microorganisms become much more resistant to antimicrobial treatments, harsh environmental conditions, and host immunity. Biofilm formation by microbial pathogens greatly enhances survival in hosts and causes chronic infections that result in persistent inflammation and tissue damages. Currently, it is believed over 80% of chronic infectious diseases are mediated by biofilms, and it is known that conventional antibiotic medications are inadequate at eradicating these biofilm-mediated infections. This situation demands new strategies for biofilm-assocd. infections, and currently, researchers focus on the development of antibiofilm agents that are specific to biofilms, but are nontoxic, because it is believed that this prevents the development of drug resistance. Here, we review the most promising antibiofilm agents undergoing intensive research and development.
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    73. 73
      Cascioferro, S.; Parrino, B.; Petri, G. L.; Cusimano, M. G.; Schillaci, D.; Di Sarno, V.; Musella, S.; Giovannetti, E.; Cirrincione, G.; Diana, P. 2,6-Disubstituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Potent Staphylococcal Biofilm Inhibitors. Eur. J. Med. Chem. 2019, 167, 200– 210,  DOI: 10.1016/j.ejmech.2019.02.007
      73
      2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent Staphylococcal biofilm inhibitors
      Cascioferro, Stella; Parrino, Barbara; Petri, Giovanna Li; Cusimano, Maria Grazia; Schillaci, Domenico; Di Sarno, Veronica; Musella, Simona; Giovannetti, Elisa; Cirrincione, Girolamo; Diana, Patrizia
      European Journal of Medicinal Chemistry (2019), 167 (), 200-210CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles, compds. I [R = H, Cl, Br; R1 = H, Me; R2 = H, 3-MeO, 4F, etc.] was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-pos. bacterial ref. strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-neg. strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compds., were able to inhibit biofilm formation of the tested Staphylococcal strains showing BIC50 lower than 10 μg/mL. In particular, compds. I [R = H, R1 = H, R2 = 2,5-diMeO; R = H, R1 = Me, R2 = 3-MeO] showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC50 values of 0.5 and 0.8 μg/mL, resp., whereas compd. I [R = Cl, R1 = H, R2 = 2,5-diMeO] was the most potent against S. aureus ATCC 6538, with a BIC50 of 0.3 μg/mL. Remarkably, these compds. showed effects in the early stages of the biofilm formation without affecting the mature biofilm of the same strains and the viability of the planktonic form. Their ability in counteracting a virulence factor (biofilm formation) without interfering with the bacterial growth in the free life form make them novel valuable anti-virulence agents.
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    74. 74
      Qin, Z.; Zhang, J.; Xu, B.; Chen, L.; Wu, Y.; Yang, X.; Shen, X.; Molin, S.; Danchin, A.; Jiang, H.; Qu, D. Structure-Based Discovery of Inhibitors of the YycG Histidine Kinase: New Chemical Leads to Combat Staphylococcus Epidermidis Infections. BMC Microbiol. 2006, 6, 96,  DOI: 10.1186/1471-2180-6-96
      74
      Structure-based discovery of inhibitors of the YycG histidine kinase: new chemical leads to combat Staphylococcus epidermidis infections
      Qin Zhiqiang; Zhang Jian; Xu Bin; Chen Lili; Wu Yang; Yang Xiaomei; Shen Xu; Molin Soeren; Danchin Antoine; Jiang Hualiang; Qu Di
      BMC microbiology (2006), 6 (), 96 ISSN:.
      BACKGROUND: Coagulase-negative Staphylococcus epidermidis has become a major frequent cause of infections in relation to the use of implanted medical devices. The pathogenicity of S. epidermidis has been attributed to its capacity to form biofilms on surfaces of medical devices, which greatly increases its resistance to many conventional antibiotics and often results in chronic infection. It has an urgent need to design novel antibiotics against staphylococci infections, especially those can kill cells embedded in biofilm. RESULTS: In this report, a series of novel inhibitors of the histidine kinase (HK) YycG protein of S. epidermidis were discovered first using structure-based virtual screening (SBVS) from a small molecular lead-compound library, followed by experimental validation. Of the 76 candidates derived by SBVS targeting of the homolog model of the YycG HATPase_c domain of S. epidermidis, seven compounds displayed significant activity in inhibiting S. epidermidis growth. Furthermore, five of them displayed bactericidal effects on both planktonic and biofilm cells of S. epidermidis. Except for one, the compounds were found to bind to the YycG protein and to inhibit its auto-phosphorylation in vitro, indicating that they are potential inhibitors of the YycG/YycF two-component system (TCS), which is essential in S. epidermidis. Importantly, all these compounds did not affect the stability of mammalian cells nor hemolytic activities at the concentrations used in our study. CONCLUSION: These novel inhibitors of YycG histidine kinase thus are of potential value as leads for developing new antibiotics against infecting staphylococci. The structure-based virtual screening (SBVS) technology can be widely used in screening potential inhibitors of other bacterial TCSs, since it is more rapid and efficacious than traditional screening technology.
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    75. 75
      Pan, B.; Huang, R.; Zheng, L.; Chen, C.; Han, S.; Qu, D.; Zhu, M.; Wei, P. Thiazolidione Derivatives as Novel Antibiofilm Agents: Design, Synthesis, Biological Evaluation, and Structure-Activity Relationships. Eur. J. Med. Chem. 2011, 46, 819– 824,  DOI: 10.1016/j.ejmech.2010.12.014
      75
      Thiazolidione derivatives as novel antibiofilm agents: Design, synthesis, biological evaluation, and structure-activity relationships
      Pan, Bin; Huang, Renzheng; Zheng, Likang; Chen, Chen; Han, Shiqing; Qu, Di; Zhu, Mingli; Wei, Ping
      European Journal of Medicinal Chemistry (2011), 46 (3), 819-824CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Rational designed novel thiazolidiones were synthesized and evaluated for antibiofilm activity. The active derivs. were not only potent inhibitors of Staphylococcus epidermidis biofilm growth but also efficient antibacterial agents. I showed 4-fold higher activity (6.25 μM) in the biofilms dispersal assay and significantly higher antibacterial activity (MIC 3.125 μM) in comparison to 3-(5-((6-(ethoxycarbonyl)-5-(benzo[1,3]dioxol-5-yl)-3-oxo-7-phenylthiazolo[3,2-a]pyrimidin-2(5H)-ylidene)methyl)furan-2-yl)benzoic acid.
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    76. 76
      Pan, B.; Huang, R.-Z.; Han, S.-Q.; Qu, D.; Zhu, M.-L.; Wei, P.; Ying, H.-J. Design, Synthesis, and Antibiofilm Activity of 2-Arylimino-3-Aryl-Thiazolidine-4-Ones. Bioorg. Med. Chem. Lett. 2010, 20, 2461– 2464,  DOI: 10.1016/j.bmcl.2010.03.013
      76
      Design, synthesis, and antibiofilm activity of 2-arylimino-3-aryl-thiazolidine-4-ones
      Pan, Bin; Huang, Ren-Zheng; Han, Shi-Qing; Qu, Di; Zhu, Ming-Li; Wei, Ping; Ying, Han-Jie
      Bioorganic & Medicinal Chemistry Letters (2010), 20 (8), 2461-2464CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A series of novel 2-arylimino-3-arylthiazolidin-4-ones was designed, synthesized, and tested for in vitro antibiofilm activity against Staphylococcus epidermidis. Among those tested, some compds. with carboxylic acid groups showed good antibiofilm activity. The structure-activity relationships revealed that incorporation of 2-phenylfuran moiety could greatly enhance antibiofilm activity of thiazolidin-4-one.
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    77. 77
      Rane, R. A.; Sahu, N. U.; Shah, C. P. Synthesis and Antibiofilm Activity of Marine Natural Product-Based 4-Thiazolidinones Derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 7131– 7134,  DOI: 10.1016/j.bmcl.2012.09.073
      77
      Synthesis and antibiofilm activity of marine natural product-based 4-thiazolidinones derivatives
      Rane, Rajesh A.; Sahu, Niteshkumar U.; Shah, Chetan P.
      Bioorganic & Medicinal Chemistry Letters (2012), 22 (23), 7131-7134CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      4-Thiazolidinones derivs. of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compds. Among the synthesized compds., some showed promising antibiofilm activity. Biol. data revealed that 1,3-thiazolidin-4-one derivs. are more potent antibiofilm agents compared to 1,3-thiazinan-4-ones. Antibiofilm activity of compds. I [Ar = C6H4OMe-4, C6H4NO2-4] (MIC = 0.78 μg/mL, each) was 3-fold superior than std. vancomycin (MIC = 3.125 μg/mL) while activity of compds. I [Ar = C6H3OH-2-OMe-4, C6H3(OH)2-2,5, C6H4F-4, C6H4Cl-4] was 2-fold (MIC = 1.56 μg/mL) against Staphylococcus aureus biofilm. Compds. I [C6H4OMe-4, C6H4NO2-4, C6H3OH-2-OMe-4, C6H3OH-3-OMe-4, C6H3(OH)2-2,5, C6H4F-4, C6H4Cl-4] showed equal antibiofilm activity against Staphylococcus epidermidis compared to std. Vancomycin (MIC = 3.125 μg/mL).
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    78. 78
      Zhao, D.; Chen, C.; Liu, H.; Zheng, L.; Tong, Y.; Qu, D.; Han, S. Biological Evaluation of Halogenated Thiazolo[3,2-a]Pyrimidin-3-One Carboxylic Acid Derivatives Targeting the YycG Histidine Kinase. Eur. J. Med. Chem. 2014, 87, 500– 507,  DOI: 10.1016/j.ejmech.2014.09.096
      78
      Biological evaluation of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivatives targeting the YycG histidine kinase
      Zhao, Dan; Chen, Chen; Liu, Huayong; Zheng, Likang; Tong, Yao; Qu, Di; Han, Shiqing
      European Journal of Medicinal Chemistry (2014), 87 (), 500-507CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      With an intention to potent inhibitors of YycG histidine kinase, a series of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivs. e. g., I, were synthesized and evaluated for their antibacterial, antibiofilm and hemolytic activities. The majority of the compds. showed good activity against Staphylococcus epidermidis and Staphylococcus aureus, with MIC values of 1.56-6.25 μM, simultaneously presented promising antiobifilm activity against S. epidermidis ATCC35984 at 50 μM. The test of inhibitory activity on YycG kinase suggested the antibacterial activities of these derivs. are based on inhibiting the enzyme activity of the YycG HK domain. The hemolytic activity test suggested these compds. exhibited in vitro antibacterial activity at non-hemolytic concns.
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    79. 79
      Siddiqui, N.; Arya, S. K.; Ahsan, W.; Azad, B. Diverse Biological Activities of Thiazoles: A Retrospect. Int.J. Drug Develop. Res. 2011, 3, 55– 57
      79
      Diverse biological activities of thiazoles: a retrospect
      Siddiqui, Nadeem; Arya, Satish Kumar; Ahsan, Waquar; Azad, Bishmillah
      International Journal of Drug Development & Research (2011), 3 (4), 55-67CODEN: IJDDA7; ISSN:0975-9344. (International Journal of Drug Development & Research)
      A review. Many compds. bearing five membered heterocyclic rings in their structure have an extensive spectrum of biol. activities. The search for new biol. active thiazole analogs continues to be an area of intensive investigation in medicinal chem. The present review describes ongoing research in search for new thiazole compds. that can prove useful for the design of future target and development of new drug mol.
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    80. 80
      da Silva, C. M.; da Silva, D. L.; Modolo, L. V.; Alves, R. B.; de Resende, M. A.; Martins, C. V. B. de; de Fátima, Â. Schiff Bases: A Short Review of Their Antimicrobial Activities. J. Advanc. Res. 2011, 2, 1– 8,  DOI: 10.1016/j.jare.2010.05.004
      There is no corresponding record for this reference.
    81. 81
      More, P. G.; Karale, N. N.; Lawand, A. S.; Narang, N.; Patil, R. H. Synthesis and Anti-Biofilm Activity of Thiazole Schiff Bases. Med. Chem. Res. 2014, 23, 790– 799,  DOI: 10.1007/s00044-013-0672-7
      81
      Synthesis and anti-biofilm activity of thiazole Schiff bases
      More, Prakash G.; Karale, Netaji N.; Lawand, Anjana S.; Narang, Naina; Patil, Rajendra H.
      Medicinal Chemistry Research (2014), 23 (2), 790-799CODEN: MCREEB; ISSN:1054-2523. (Birkhaeuser Boston)
      A series of thiazole Schiff bases have been synthesized by reacting 4-(o-methoxyphenyl)-2-aminothiazole and R substituted salicylaldehyde (R = H, 3-Me, 4-Me, 5-Me, 3-OMe and 5-Br) or 2-hydroxy-1-naphthaldehyde under microwave irradn. (a green chem. approach). The compds. were characterized by spectral (UV-Vis, IR, 1H NMR, 13C NMR and GC-MS) and thermal analyses, and tested for the evaluation of anti-biofilm activity against Pseudomonas aeruginosa and anti-bacterial activity against Gram pos. (Bacillus subtilis NCIM 2063) and Gram neg. (Escherichia coli NCIM 2931) bacteria. The scanning electron microscopic images of the bacterial surfaces have shown that the Schiff bases have impeded the biofilm formation at 50-100 μg/mL concn., without affecting the growth of the cells (and thus behave as antiquorum sensing agents). Confocal laser scanning microscopy has also confirmed the biofilm inhibition. The anti-biofilm and anti-bacterial activities of the Schiff bases are promising in the design and bio-fabrication of medical devices to combat the biofilm-forming pathogenic organisms.
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    82. 82
      Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent Applications of 1,3-Thiazole Core Structure in the Identification of New Lead Compounds and Drug Discovery. Eur. J. Med. Chem. 2015, 97, 699– 718,  DOI: 10.1016/j.ejmech.2015.04.015
      82
      Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery
      Ayati, Adile; Emami, Saeed; Asadipour, Ali; Shafiee, Abbas; Foroumadi, Alireza
      European Journal of Medicinal Chemistry (2015), 97 (), 699-718CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. 1,3-Thiazole is one of the most important scaffolds in heterocyclic chem. and drug design and discovery. It is widely found in diverse pharmacol. active substances and in some naturally-occurring compds. Thiazole is a versatile building-block for lead generation, and is easily access of diverse derivs. for subsequent lead optimization. In the recent years, many thiazole derivs. have been synthesized and subjected to varied biol. activities. In this article we intended to review the most important biol. effects of thiazole-based compds. and highlight their roles in new leads identification and drug discovery. This article is also intended to help researches for finding potential future directions on the development of more potent and specific analogs of thiazole-based compds. for various biol. targets.
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    83. 83
      Stefanska, J.; Nowicka, G.; Struga, M.; Szulczyk, D.; Koziol, A. E.; Augustynowicz-Kopec, E.; Napiorkowska, A.; Bielenica, A.; Filipowski, W.; Filipowska, A.; Drzewiecka, A.; Giliberti, G.; Madeddu, S.; Boi, S.; La Colla, P.; Sanna, G. Antimicrobial and Anti-Biofilm Activity of Thiourea Derivatives Incorporating a 2-Aminothiazole Scaffold. Chem. Pharm. Bull. 2015, 63, 225– 236,  DOI: 10.1248/cpb.c14-00837
      83
      Antimicrobial and Anti-biofilm Activity of Thiourea Derivatives Incorporating a 2-Aminothiazole Scaffold
      Stefanska, Joanna; Nowicka, Grazyna; Struga, Marta; Szulczyk, Daniel; Koziol, Anna Eugenia; Augustynowicz-Kopec, Ewa; Napiorkowska, Agnieszka; Bielenica, Anna; Filipowski, Wojciech; Filipowska, Anna; Drzewiecka, Aleksandra; Giliberti, Gabriele; Madeddu, Silvia; Boi, Stefano; La Colla, Paolo; Sanna, Giuseppina
      Chemical & Pharmaceutical Bulletin (2015), 63 (3), 225-236CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)
      A series of new thiourea derivs. of 1,3-thiazole I [R = 2-BrC6H4, cyclohexyl, CH2C6H5, ethoxycarbonyl, etc.] have been synthesized. All obtained compds. were tested in vitro against a no. of microorganisms, including Gram-pos. cocci, Gram-neg. rods and Candida albicans. The compds. I were also tested for their in vitro tuberculostatic activity against the Mycobacterium tuberculosis H37Rv strain, as well as two 'wild' strains isolated from tuberculosis patients. The compds. I (R = 3,4-Cl2C6H3, 3-Cl-4-FC6H3) showed significant inhibition against Gram-pos. cocci (std. strains and hospital strain). The range of MIC values is 2-32 μg/mL. Products I (R = 3,4-Cl2C6H3, 3-Cl-4-FC6H3) effectively inhibited the biofilm formation of both methicillin-resistant and std. strains of S. epidermidis. The halogen atom, esp. at the third position of the Ph group, is significantly important for this antimicrobial activity. Moreover, all obtained compds. resulted in cytotoxicity and antiviral activity on a large set of DNA and RNA viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and other several important human pathogens. The compd. I (R = cyclohexyl) showed activity against HIV-1 and Coxsackievirus type B5. Seven compds. resulted in cytotoxicity against MT-4 cells (CC50<10 μM).
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    84. 84
      Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010. J. Nat. Prod. 2012, 75, 311– 335,  DOI: 10.1021/np200906s
      84
      Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
      Newman, David J.; Cragg, Gordon M.
      Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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    85. 85
      Martins, A.; Vieira, H.; Gaspar, H.; Santos, S. Marketed Marine Natural Products in the Pharmaceutical and Cosmeceutical Industries: Tips for Success. Mar. Drugs 2014, 12, 1066– 1101,  DOI: 10.3390/md12021066
      85
      Marketed marine natural products in the pharmaceutical and cosmeceutical industries: tips for success
      Martins Ana; Vieira Helena; Gaspar Helena; Santos Susana
      Marine drugs (2014), 12 (2), 1066-101 ISSN:.
      The marine environment harbors a number of macro and micro organisms that have developed unique metabolic abilities to ensure their survival in diverse and hostile habitats, resulting in the biosynthesis of an array of secondary metabolites with specific activities. Several of these metabolites are high-value commercial products for the pharmaceutical and cosmeceutical industries. The aim of this review is to outline the paths of marine natural products discovery and development, with a special focus on the compounds that successfully reached the market and particularly looking at the approaches tackled by the pharmaceutical and cosmetic companies that succeeded in marketing those products. The main challenges faced during marine bioactives discovery and development programs were analyzed and grouped in three categories: biodiversity (accessibility to marine resources and efficient screening), supply and technical (sustainable production of the bioactives and knowledge of the mechanism of action) and market (processes, costs, partnerships and marketing). Tips to surpass these challenges are given in order to improve the market entry success rates of highly promising marine bioactives in the current pipelines, highlighting what can be learned from the successful and unsuccessful stories that can be applied to novel and/or ongoing marine natural products discovery and development programs.
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    86. 86
      Cascioferro, S.; Attanzio, A.; Di Sarno, V.; Musella, S.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. New 1,2,4-Oxadiazole Nortopsentin Derivatives with Cytotoxic Activity. Mar. Drugs 2019, 17, 35,  DOI: 10.3390/md17010035
      86
      New 1,2,4-oxadiazole nortopsentin derivatives with cytotoxic activity
      Cascioferro, Stella; Attanzio, Alessandro; Di Sarno, Veronica; Musella, Simona; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara
      Marine Drugs (2019), 17 (1), 35pp.CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      New analogs of nortopsentin, a natural 2,4-bis(3'-indolyl)imidazole alkaloid, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety and in which a 7-azaindole portion substituted the original indole moiety were efficiently synthesized. Among all derivs., prescreened against the HCT-116 colon rectal carcinoma cell line, the two most active compds. were selected and further investigated in different human tumor cells showing IC50 values in the micromolar and submicromolar range. Flow cytometric anal. of propidium iodide-stained MCF-7 cells demonstrated that both the active derivs. caused cell cycle arrest in the G0-G1 phase. The cell death mechanism induced by the compds. was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and obsd. morphol. evaluation using acridine orange/ethidium bromide double staining. Moreover, further tested on intestinal normal-like differentiated Caco-2 cell line, they exhibited preferential toxicity towards cancer cells.
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    87. 87
      Spanò, V.; Attanzio, A.; Cascioferro, S.; Carbone, A.; Montalbano, A.; Barraja, P.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs. Mar. Drugs 2016, 14, 226,  DOI: 10.3390/md14120226
      87
      Synthesis and antitumor activity of new thiazole nortopsentin analogs
      Spano, Virginia; Attanzio, Alessandro; Cascioferro, Stella; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara
      Marine Drugs (2016), 14 (12), 226/1-226/18CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion were conveniently synthesized. Among these, three derivs. showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compds. acted as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population.
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    88. 88
      Parrino, B.; Carbone, A.; Ciancimino, C.; Spanò, V.; Montalbano, A.; Barraja, P.; Cirrincione, G.; Diana, P.; Sissi, C.; Palumbo, M.; Pinato, O.; Pennati, M.; Beretta, G.; Folini, M.; Matyus, P.; Balogh, B.; Zaffaroni, N. Water-Soluble Isoindolo[2,1-a]Quinoxalin-6-Imines: In Vitro Antiproliferative Activity and Molecular Mechanism(s) of Action. Eur. J. Med. Chem. 2015, 94, 149– 162,  DOI: 10.1016/j.ejmech.2015.03.005
      88
      Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: In vitro antiproliferative activity and molecular mechanism(s) of action
      Parrino, Barbara; Carbone, Anna; Ciancimino, Cristina; Spano, Virginia; Montalbano, Alessandra; Barraja, Paola; Cirrincione, Girolamo; Diana, Patrizia; Sissi, Claudia; Palumbo, Manlio; Pinato, Odra; Pennati, Marzia; Beretta, Giovanni; Folini, Marco; Matyus, Peter; Balogh, Balazs; Zaffaroni, Nadia
      European Journal of Medicinal Chemistry (2015), 94 (), 149-162CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Water-sol. isoindoloquinoxaline (IIQ) imines and the corresponding acetates were conveniently prepd. from the key intermediates 2-(2'-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compds. showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivs., methoxy substituents at positions 3 and 8 or/and 9 were esp. effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were assocd. to IIQ-mediated impairment of tubulin polymn. at pharmacol. significant concns. of tested compds. In addn., impaired DNA topoisomerase I functions and perturbation in telomere architecture were obsd. in cells exposed to micromolar concns. of IIQ derivs. The above results suggest that IIQ derivs. exhibit multi-target cytotoxic activities.
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    89. 89
      Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Lee, T.-H.; Kim, J.-G.; Shin, D.; Sim, C. J.; Shin, J. Antimicrobial Activity and Cytotoxicity of Bis(Indole) Alkaloids from the Sponge Spongosorites Sp. Biol. Pharm. Bull. 2006, 29, 570– 573,  DOI: 10.1248/bpb.29.570
      89
      Antimicrobial activity and cytotoxicity of bis(indole) alkaloids from the sponge Spongosorites sp.
      Oh, Ki-Bong; Mar, Woongchon; Kim, Sanghee; Kim, Ji-Yun; Lee, Tae-Hoon; Kim, Jae-Gyu; Shin, Daehyun; Sim, Chung J.; Shin, Jongheon
      Biological & Pharmaceutical Bulletin (2006), 29 (3), 570-573CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
      Bis(indole) alkaloids, of the topsentin class (1-4) and hamacanthin class (5-9), isolated from the marine sponge Spongosorites sp. were investigated using several biol. assays. In the evaluation of antimicrobial activity against various strains of bacteria and fungi, compds. of the hamacanthin class exhibited more potent antibacterial activity than those of the topsentin class. Deoxytopsentin (1) and hamacanthin A (5) also exhibited significant antibacterial activity against methicillin-resistant Staphylococcus aureus, with MIC values of less than 12.5 μg/mL. In the antifungal activity test, hamacanthins, esp. hamacanthin A (5), showed potent inhibitory activity against medically important pathogenic fungi. In contrast, all of the topsentins (1-4) were inactive against fungal growth. These compds. (1-9) also exhibited moderate cytotoxicity against cancer cell lines at concns. between 1.1 and >20 μg/mL.
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    90. 90
      Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Oh, M.-N.; Kim, J.-G.; Shin, D.; Sim, C. J.; Shin, J. Bis(Indole) Alkaloids as Sortase A Inhibitors from the Sponge Spongosorites Sp. Bioorg. Med. Chem. Lett. 2005, 15, 4927– 4931,  DOI: 10.1016/j.bmcl.2005.08.021
      90
      Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp.
      Oh, Ki-Bong; Mar, Woongchon; Kim, Sanghee; Kim, Ji-Yun; Oh, Mi-Na; Kim, Jae-Gyu; Shin, Daehyun; Sim, Chung J.; Shin, Jongheon
      Bioorganic & Medicinal Chemistry Letters (2005), 15 (22), 4927-4931CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A new bis(indole) alkaloid (I) of the hamacanthin class along with the previously reported compds. of the related structural classes, topsentin class and hamacanthin class, was isolated from the marine sponge Spongosorites sp. and their inhibitory activities toward sortase A (SrtA) that play key roles in cell-wall protein anchoring and virulence in Staphylococcus aureus were evaluated. Our studies have identified a series of SrtA inhibitors, providing the basis for further development of potent inhibitors. The preliminary structure-activity relationship, to elucidate the essential structural requirements, has been described. The fibronectin-binding activity data highlight the potential of these compds. for the treatment of S. aureus infections via inhibition of SrtA activity.
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    91. 91
      Gul, W.; Hamann, M. T. Indole Alkaloid Marine Natural Products: An Established Source of Cancer Drug Leads with Considerable Promise for the Control of Parasitic, Neurological and Other Diseases. Life Sci. 2005, 78, 442– 453,  DOI: 10.1016/j.lfs.2005.09.007
      91
      Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases
      Gul, Waseem; Hamann, Mark T.
      Life Sciences (2005), 78 (5), 442-453CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)
      A review. The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biol. activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacol. activities.
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    92. 92
      Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. A New Bis-(Indole) Alkaloid from a Deep-Water Marine Sponge of the Genus Spongosorites. J. Org. Chem. 1992, 57, 4772– 4775,  DOI: 10.1021/jo00043a045
      92
      A new bis-(indole) alkaloid from a deep-water marine sponge of the genus Spongosorites
      Wright, Amy E.; Pomponi, Shirley A.; Cross, Sue S.; McCarthy, Peter
      Journal of Organic Chemistry (1992), 57 (17), 4772-5CODEN: JOCEAH; ISSN:0022-3263.
      A new bis-(indole)-alkaloid, named dragmacidin d, has been isolated from a deep water marine sponge of the genus Spongosorites. Its structure was detd. through spectroscopic methods, including one and two dimensional NMR spectroscopy. It inhibits the growth of the feline leukemia virus, the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans and the P388 and A549 tumor cell lines.
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    93. 93
      Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.; Jung, J. H. Cytotoxic Bisindole Alkaloids from a Marine Sponge Spongosorites Sp. J. Nat. Prod. 2005, 68, 711– 715,  DOI: 10.1021/np049577a
      93
      Cytotoxic bisindole alkaloids from a marine sponge Spongosorites sp.
      Bao, Baoquan; Sun, Qishi; Yao, Xinsheng; Hong, Jongki; Lee, Chong-O.; Sim, Chung Ja; Im, Kwang Sik; Jung, Jee H.
      Journal of Natural Products (2005), 68 (5), 711-715CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
      Three new bisindole alkaloids of the hamacanthin class (I-III) and one new bisindole alkaloid of the topsentin class (VI) were isolated along with known bisindole alkaloids (e.g. IV-V) from the MeOH ext. of a marine sponge Spongosorites sp. by bioactivity-guided fractionation. The planar structures were established on the basis of NMR, MS, and IR spectroscopic analyses. Configurations of compds. I-IV were derived from 1H NMR data and optical rotation. Compds. I, IV, V, and isobromodeoxytopsentin showed moderate to significant cytotoxicity against five human tumor cell lines, and compds. I-V showed weak antibacterial activity against clin. isolated methicillin-resistant strains.
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    94. 94
      Sun, H. H.; Sakemi, S.; Gunasekera, S.; Kashman, Y.; Lui, M.; Burres, N.; McCarthy, P. Bis-Indole Imidazole Compounds Which Are Useful Antitumor and Antimicrobial Agents. US 4970226A, 1990.
      There is no corresponding record for this reference.
    95. 95
      Carbone, A.; Parrino, B.; Cusimano, M. G.; Spanò, V.; Montalbano, A.; Barraja, P.; Schillaci, D.; Cirrincione, G.; Diana, P.; Cascioferro, S. New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation. Mar. Drugs 2018, 16, 274,  DOI: 10.3390/md16080274
      95
      New thiazole nortopsentin analogues inhibit bacterial biofilm formation
      Carbone, Anna; Parrino, Barbara; Cusimano, Maria Grazia; Spano, Virginia; Montalbano, Alessandra; Barraja, Paola; Schillaci, Domenico; Cirrincione, Girolamo; Diana, Patrizia; Cascioferro, Stella
      Marine Drugs (2018), 16 (8), 274/1-274/15CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      New thiazole nortopsentin analogs I (R = H, OCH3, Br, F; R1 = CH2CH2NHCO2t-Bu, CH2CH2NH2, etc.; R2 = H, Me, etc.) were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-pos. and Gram-neg. pathogens. All compds. were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivs. I (R = H, R1 = CH2CH2NHCO2t-Bu, R2 = H; R = H, R1 = CO2t-Bu, R2 = CH2CH2OCH3) elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40-2.03 μM. The new compds. I showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.
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    96. 96
      Mazmanian, S. K.; Liu, G.; Jensen, E. R.; Lenoy, E.; Schneewind, O. Staphylococcus Aureus Sortase Mutants Defective in the Display of Surface Proteins and in the Pathogenesis of Animal Infections. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 5510– 5515,  DOI: 10.1073/pnas.080520697
      96
      Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections
      Mazmanian, Sarkis K.; Liu, Gwen; Jensen, Eric R.; Lenoy, Eileen; Schneewind, Olaf
      Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (10), 5510-5515CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Many Gram-pos. bacteria covalently tether their surface adhesins to the cell wall peptidoglycan. We find that surface proteins of Staphylococcus aureus are linked to the cell wall by sortase, an enzyme that cleaves polypeptides at a conserved LPXTG motif. S. aureus mutants lacking sortase fail to process and display surface proteins and are defective in the establishment of infections. Thus, the cell wall envelope of Gram-pos. bacteria represents a surface organelle responsible for interactions with the host environment during the pathogenesis of bacterial infections.
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    97. 97
      Cascioferro, S.; Raffa, D.; Maggio, B.; Raimondi, M. V.; Schillaci, D.; Daidone, G. Sortase A Inhibitors: Recent Advances and Future Perspectives. J. Med. Chem. 2015, 58, 9108– 9123,  DOI: 10.1021/acs.jmedchem.5b00779
      97
      Sortase A Inhibitors: Recent Advances and Future Perspectives
      Cascioferro, Stella; Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Schillaci, Domenico; Daidone, Giuseppe
      Journal of Medicinal Chemistry (2015), 58 (23), 9108-9123CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Here, we describe the most promising small synthetic org. compds. that act as potent Sortase A inhibitors and cater the potential to be developed as antivirulence drugs. Sortase A is a polypeptide of 206 amino acids, which catalyzes two sequential reactions: (i) thioesterification and (ii) transpeptidation. Sortase A is involved in the process of bacterial adhesion by anchoring LPXTG-contg. proteins to lipid II. Sortase A inhibitors do not affect bacterial growth, but they restrain the virulence of pathogenic bacterial strains, thereby preventing infections caused by Staphylococcus aureus or other Gram-pos. bacteria. The efficacy of the most promising inhibitors needs to be comprehensively evaluated in in vivo models of infection, in order to select compds. eligible for the treatment of bacterial infections in humans.
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    98. 98
      Chen, L.; Yang, D.; Pan, Z.; Lai, L.; Liu, J.; Fang, B.; Shi, S. Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative. Chem. Biol. Drug Des. 2015, 86, 239– 245,  DOI: 10.1111/cbdd.12486
      98
      Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative
      Chen, Liangzhu; Yang, Dexue; Pan, Zhikun; Lai, Lihong; Liu, Jianhua; Fang, Binghu; Shi, Shuning
      Chemical Biology & Drug Design (2015), 86 (2), 239-245CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
      A series of novel hybrid mols. between sulfonamides and active antimicrobial 14-o-(3-carboxy-phenylsulfide)-mutilin were synthesized, and their in vitro antibacterial activities were evaluated by the broth microdilution. Results indicated that these compds. displayed potent antimicrobial activities in vitro against various drug-susceptible and drug-resistant Gram-pos. bacteria such as Staphylococci and streptococci, including methicillin-resistant Staphylococcus aureus, and mycoplasma. In particular, sulfapyridine analog (6c) exhibited more potent inhibitory activity against Gram-pos. bacteria and mycoplasma, including Staphylococcus aureus (MIC = 0.016-0.063 μg/mL), methicillin-resistant Staphylococcus aureus (MIC = 0.016 μg/mL), Streptococcus pneumoniae (MIC = 0.032-0.063 μg/mL), Mycoplasma gallisepticum (MIC = 0.004 μg/mL), with respect to other synthesized compds. and ref. drugs sulfonamide (MIC = 8-128 μg/mL) and valnemulin (MIC = 0.004-0.5 μg/mL). Furthermore, comparison between MIC values of pleuromutilin-sulfonamide hybrids 6a-f with pleuromutilin parent compd. 3 revealed that these modifications at 14 position side chain of the pleuromutilin with benzene sulfonamide could greatly improve the antibacterial activity esp. against Gram-positives.
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    99. 99
      Klahn, P.; Brönstrup, M. Bifunctional Antimicrobial Conjugates and Hybrid Antimicrobials. Nat. Prod. Rep. 2017, 34, 832– 885,  DOI: 10.1039/C7NP00006E
      99
      Bifunctional antimicrobial conjugates and hybrid antimicrobials
      Klahn, P.; Broenstrup, M.
      Natural Product Reports (2017), 34 (7), 832-885CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
      A review. Novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. An innovative mol. design strategy for novel antibiotic drugs is based on the hybridization of an antibiotic with a second functional entity. Such conjugates can be grouped into two major categories. In the first category (antimicrobial hybrids), both functional elements of the hybrid exert antimicrobial activity. Due to the dual targeting, resistance development can be significantly impaired, the pharmacokinetic properties can be superior compared to combination therapies with the single antibiotics, and the antibacterial potency is often enhanced in a synergistic manner. In the second category (antimicrobial conjugates), one functional moiety controls the accumulation of the other part of the conjugate, e.g. by mediating an active transport into the bacterial cell or blocking the efflux. This approach is mostly applied to translocate compds. across the cell envelope of Gram-neg. bacteria through membrane-embedded transporters (e.g. siderophore transporters) that provide nutrition and signalling compds. to the cell. Such 'Trojan Horse' approaches can expand the antibacterial activity of compds. against Gram-neg. pathogens, or offer new options for natural products that could not be developed as standalone antibiotics, e.g. due to their toxicity.
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    100. 100
      Gondru, R.; Sirisha, K.; Raj, S.; Gunda, S. K.; Kumar, C. G.; Pasupuleti, M.; Bavantula, R. Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole-Thiazole Hybrids as Antimicrobial and Antibiofilm Agents. ChemistrySelect 2018, 3, 8270– 8276,  DOI: 10.1002/slct.201801391
      100
      Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole-Thiazole Hybrids as Antimicrobial and Antibiofilm Agents
      Gondru, Ramesh; Sirisha, K.; Raj, Sneha; Gunda, Shravan Kumar; Kumar, C. Ganesh; Pasupuleti, Mukesh; Bavantula, Rajitha
      ChemistrySelect (2018), 3 (28), 8270-8276CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)
      In the present study, a series of novel pyrazole-thiazole hybrids I (R = Ph, 4-MeC6H4, 4-MeOC6H4, etc.) were designed, synthesized and assessed for their in vitro antimicrobial activity against both Gram-pos. and Gram-neg. pathogenic bacterial and fungal strains. Compds. I (R = 4-MeC6H4, 4-BrC6H4, 8-bromocoumarinyl, 6,8-dibromocoumarinyl) exhibited promising inhibitory activity against the tested bacterial strains with min. inhibitory concn. (MIC)/min. bactericidal concn. (MBC) spectrum of 1.9/7.8 μg/mL to 3.9/7.8 μg/mL. The compds. I (R = 4-MeC6H4, 4-MeOC6H4, benzo[f]coumarinyl, 8-bromocoumarinyl) showed their inhibitory potency against various Candida strains with MIC/min. fungicidal concn. (MFC) values of 3.9/7.8 μg/mL. Also, anti-biofilm and toxicity profile of the compds. was also tested. The biofilm inhibition results revealed that the compd. I (R = benzo[f]coumarinyl) exhibited promising activity with an IC50 value of 11.8 μM against S. aureus MTCC 96, while compd. compd. I (R = 8-bromocoumarinyl) showed significant activity against S. aureus MLS16 MTCC 2940, K. planticola MTCC 530 and C. albicans MTCC 3017 with IC50 values of 12, 14 and 16 μM, resp. The present study has emphasized that thiazole-pyrazole hybrids with benzothiazole and coumarin scaffolds can be a novel and potent class of mols. with potential biol. activities.
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    101. 101
      Horwich, A. L.; Farr, G. W.; Fenton, W. A. GroEL-GroES-Mediated Protein Folding. Chem. Rev. 2006, 106, 1917– 1930,  DOI: 10.1021/cr040435v
      101
      GroEL-GroES-mediated protein folding
      Horwich, Arthur L.; Farr, George W.; Fenton, Wayne A.
      Chemical Reviews (Washington, DC, United States) (2006), 106 (5), 1917-1930CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Chaperonin-mediated folding is an essential ATP-dependent reaction that provides kinetic assistance to the process of protein folding o the native state in a variety of cellular compartments. The Escherichia coli reaction is carried out by a megadalton-sized double ring "machine" consisting of chaperonin GroEL in complex with its co-chaperonin GroES. The binding of GroES to GroEL is ATP-dependent with the nucleotide rapidly and cooperatively binding to 7 sites on the GroEL ring. Here, the catalytic mechanism of GroEL-GroES-mediated protein folding is discussed along with a more detailed consideration of the transition between polypeptide binding in an open ring and productive protein folding in a co-chaperone-encapsulated one. The free energy of binding of the γ-phosphate of ATP functions as a crit. element of the folding trigger. The bulk of existing evidence appears to support a model of GroEL action in which ATP and GroES binding drive major conformational changes in GroEL that simultaneously and immediately release a substrate protein from the apical binding sites and initiate refolding.
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    102. 102
      Johnson, S. M.; Sharif, O.; Mak, P. A.; Wang, H.-T.; Engels, I. H.; Brinker, A.; Schultz, P. G.; Horwich, A. L.; Chapman, E. A Biochemical Screen for GroEL/GroES Inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 786– 789,  DOI: 10.1016/j.bmcl.2013.12.100
      102
      A biochemical screen for GroEL/GroES inhibitors
      Johnson, Steven M.; Sharif, Orzala; Mak, Puiying Annie; Wang, Hsiao-Ting; Engels, Ingo H.; Brinker, Achim; Schultz, Peter G.; Horwich, Arthur L.; Chapman, Eli
      Bioorganic & Medicinal Chemistry Letters (2014), 24 (3), 786-789CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      High-throughput screening of 700,000 small mols. has identified 235 inhibitors of the GroEL/GroES-mediated refolding cycle. Dose-response anal. of a subset of these hits revealed that 21 compds. are potent inhibitors of GroEL/GroES-mediated refolding (IC50 <10 μM). The screening results presented herein represent the first steps in a broader aim of developing mol. probes to study chaperonin biochem. and physiol.
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    103. 103
      Abdeen, S.; Salim, N.; Mammadova, N.; Summers, C. M.; Frankson, R.; Ambrose, A. J.; Anderson, G. G.; Schultz, P. G.; Horwich, A. L.; Chapman, E.; Johnson, S. M. GroEL/ES Inhibitors as Potential Antibiotics. Bioorg. Med. Chem. Lett. 2016, 26, 3127– 3134,  DOI: 10.1016/j.bmcl.2016.04.089
      103
      GroEL/ES inhibitors as potential antibiotics
      Abdeen, Sanofar; Salim, Nilshad; Mammadova, Najiba; Summers, Corey M.; Frankson, Rochelle; Ambrose, Andrew J.; Anderson, Gregory G.; Schultz, Peter G.; Horwich, Arthur L.; Chapman, Eli; Johnson, Steven M.
      Bioorganic & Medicinal Chemistry Letters (2016), 26 (13), 3127-3134CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      We recently reported results from a high-throughput screening effort that identified 235 inhibitors of the Escherichia coli GroEL/ES chaperonin system [Bioorg. Med. Chem. Lett.2014, 24, 786]. As the GroEL/ES chaperonin system is essential for growth under all conditions, we reasoned that targeting GroEL/ES with small mol. inhibitors could be a viable antibacterial strategy. Extending from our initial screen, we report here the antibacterial activities of 22 GroEL/ES inhibitors against a panel of Gram-pos. and Gram-neg. bacteria, including E. coli, Bacillus subtilis, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae. GroEL/ES inhibitors were more effective at blocking the proliferation of Gram-pos. bacteria, in particular S. aureus, where lead compds. exhibited antibiotic effects from the low-μM to mid-nM range. While several compds. inhibited the human HSP60/10 refolding cycle, some were able to selectively target the bacterial GroEL/ES system. Despite inhibiting HSP60/10, many compds. exhibited low to no cytotoxicity against human liver and kidney cell lines. Two lead candidates emerged from the panel, that exhibit >50-fold selectivity for inhibiting S. aureus growth compared to liver or kidney cell cytotoxicity. These compds. inhibited drug-sensitive and methicillin-resistant S. aureus strains with potencies comparable to vancomycin, daptomycin, and streptomycin, and are promising candidates to explore for validating the GroEL/ES chaperonin system as a viable antibiotic target.
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    104. 104
      Kim, S.; Lieberman, T. D.; Kishony, R. Alternating Antibiotic Treatments Constrain Evolutionary Paths to Multidrug Resistance. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 14494– 14499,  DOI: 10.1073/pnas.1409800111
      104
      Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance
      Kim, Seungsoo; Lieberman, Tami D.; Kishony, Roy
      Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (40), 14494-14499CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Alternating antibiotic therapy, in which pairs of drugs are cycled during treatment, has been suggested as a means to inhibit the evolution of de novo resistance while avoiding the toxicity assocd. with more traditional combination therapy. However, it remains unclear under which conditions and by what means such alternating treatments impede the evolution of resistance. Here, the authors tracked multistep evolution of resistance in replicate populations of Staphylococcus aureus during 22 d of continuously increasing single, mixed, and alternating drug treatment. In all three tested drug pairs, the alternating treatment reduced the overall rate of resistance by slowing the acquisition of resistance to one of the two component drugs, sometimes as effectively as mixed treatment. This slower rate of evolution is reflected in the genome-wide mutational profiles; under alternating treatments, bacteria acquire mutations in different genes than under corresponding single-drug treatments. To test whether this obsd. constraint on adaptive paths reflects trade-offs in which resistance to one drug is accompanied by sensitivity to a second drug, we profiled many single-step mutants for cross-resistance. Indeed, the av. cross-resistance of single-step mutants can help predict whether or not evolution was slower in alternating drugs. Together, these results show that despite the complex evolutionary landscape of multidrug resistance, alternating-drug therapy can slow evolution by constraining the mutational paths toward resistance.
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    105. 105
      Yeswanth, S.; Chandra Sekhar, K.; Chaudhary, A.; Sarma, P. V. G. K. Anti-Microbial and Anti-Biofilm Activity of a Novel Dibenzyl (Benzo[d] Thiazol-2-yl-(Hydroxy)-Methyl) Phosphonate by Inducing Protease Expression in Staphylococcus Aureus. Med. Chem. Res. 2018, 27, 785– 795,  DOI: 10.1007/s00044-017-2102-8
      105
      Anti-microbial and Anti-biofilm activity of a novel Dibenzyl (benzo[d] thiazol-2-yl (hydroxy) methyl) phosphonate by inducing protease expression in Staphylococcus aureus
      Yeswanth, Sthanikam; Chandra Sekhar, Kuruva; Chaudhary, Abhijit; Sarma, Potukuchi Venkata Gurunadha Krishna
      Medicinal Chemistry Research (2018), 27 (3), 785-795CODEN: MCREEB; ISSN:1054-2523. (Springer)
      In the present study a novel Dibenzyl (benzo[d]thiazol-2-yl(hydroxy)methyl) phosphonate (3b) derived from α-Hydroxyphosphonate exhibited anti-Staphylococcus aureus and anti-biofilm properties against penicillin, ampicillin and methicillin-resistant strains of S. aureus. The compd. 3b showed Min. inhibitory concn. (MIC90) at 160 ± 1 μg/mL and LD (LD50) at 80 ± 1 μg/mL. S. aureus growing as planktonic culture shows a formation of aggregates which is the prerequisite for the formation of biofilms, the compd. 3b disrupted aggregates and cleared all the preformed planktonic biofilms and prevented their recurrence. The SDS-PAGE anal. of compd. 3b treated S. aureus showed gradual lysis of total proteins. The zymogram anal. indicated overexpression of proteases which is the principle reason for lysis of total proteins of S. aureus on incubation with compd. 3b. Further, the dot blot anal. indicated complete lysis of Protein-A in the culture filtrate of all the drug-resistant strains of S. aureus a prominent virulence factor and biofilm forming protein. All these features exhibited by compd. 3b makes it as a potential therapeutic mol. in the treatment of S. aureus infections.
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    106. 106
      Hymes, J. P.; Klaenhammer, T. R. Stuck in the Middle: Fibronectin-Binding Proteins in Gram-Positive Bacteria. Front. Microbiol. 2016, 7, 1504,  DOI: 10.3389/fmicb.2016.01504
      106
      Stuck in the Middle: Fibronectin-Binding Proteins in Gram-Positive Bacteria
      Hymes Jeffrey P; Klaenhammer Todd R
      Frontiers in microbiology (2016), 7 (), 1504 ISSN:1664-302X.
      Fibronectin is a multidomain glycoprotein found ubiquitously in human body fluids and extracellular matrices of a variety of cell types from all human tissues and organs, including intestinal epithelial cells. Fibronectin plays a major role in the regulation of cell migration, tissue repair, and cell adhesion. Importantly, fibronectin also serves as a common target for bacterial adhesins in the gastrointestinal tract. Fibronectin-binding proteins (FnBPs) have been identified and characterized in a wide variety of host-associated bacteria. Single bacterial species can contain multiple, diverse FnBPs. In pathogens, some FnBPs contribute to virulence via host cell attachment, invasion, and interference with signaling pathways. Although FnBPs in commensal and probiotic strains are not sufficient to confer virulence, they are essential for attachment to their ecological niches. Here we describe the interaction between human fibronectin and bacterial adhesins by highlighting the FnBPs of Gram-positive pathogens and commensals. We provide an overview of the occurrence and diversity of FnBPs with a focus on the model pathogenic organisms in which FnBPs are most characterized. Continued investigation of FnBPs is needed to fully understand their divergence and specificity in both pathogens and commensals.
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    107. 107
      Franklin, M. J.; Nivens, D. E.; Weadge, J. T.; Howell, P. L. Biosynthesis of the Pseudomonas Aeruginosa Extracellular Polysaccharides, Alginate, Pel, and Psl. Front. Microbiol. 2011, 2, 167,  DOI: 10.3389/fmicb.2011.00167
      107
      Biosynthesis of the Pseudomonas aeruginosa Extracellular Polysaccharides, Alginate, Pel, and Psl
      Franklin Michael J; Nivens David E; Weadge Joel T; Howell P Lynne
      Frontiers in microbiology (2011), 2 (), 167 ISSN:.
      Pseudomonas aeruginosa thrives in many aqueous environments and is an opportunistic pathogen that can cause both acute and chronic infections. Environmental conditions and host defenses cause differing stresses on the bacteria, and to survive in vastly different environments, P. aeruginosa must be able to adapt to its surroundings. One strategy for bacterial adaptation is to self-encapsulate with matrix material, primarily composed of secreted extracellular polysaccharides. P. aeruginosa has the genetic capacity to produce at least three secreted polysaccharides; alginate, Psl, and Pel. These polysaccharides differ in chemical structure and in their biosynthetic mechanisms. Since alginate is often associated with chronic pulmonary infections, its biosynthetic pathway is the best characterized. However, alginate is only produced by a subset of P. aeruginosa strains. Most environmental and other clinical isolates secrete either Pel or Psl. Little information is available on the biosynthesis of these polysaccharides. Here, we review the literature on the alginate biosynthetic pathway, with emphasis on recent findings describing the structure of alginate biosynthetic proteins. This information combined with the characterization of the domain architecture of proteins encoded on the Psl and Pel operons allowed us to make predictive models for the biosynthesis of these two polysaccharides. The results indicate that alginate and Pel share certain features, including some biosynthetic proteins with structurally or functionally similar properties. In contrast, Psl biosynthesis resembles the EPS/CPS capsular biosynthesis pathway of Escherichia coli, where the Psl pentameric subunits are assembled in association with an isoprenoid lipid carrier. These models and the environmental cues that cause the cells to produce predominantly one polysaccharide over the others are subjects of current investigation.
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    108. 108
      Colvin, K. M.; Irie, Y.; Tart, C. S.; Urbano, R.; Whitney, J. C.; Ryder, C.; Howell, P. L.; Wozniak, D. J.; Parsek, M. R. The Pel and Psl Polysaccharides Provide Pseudomonas Aeruginosa Structural Redundancy within the Biofilm Matrix. Environ. Microbiol. 2012, 14, 1913– 1928,  DOI: 10.1111/j.1462-2920.2011.02657.x
      108
      The Pel and Psl polysaccharides provide Pseudomonas aeruginosa structural redundancy within the biofilm matrix
      Colvin, Kelly M.; Irie, Yasuhiko; Tart, Catherine S.; Urbano, Rodolfo; Whitney, John C.; Ryder, Cynthia; Howell, P. Lynne; Wozniak, Daniel J.; Parsek, Matthew R.
      Environmental Microbiology (2012), 14 (8), 1913-1928CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
      Summary : Extracellular polysaccharides comprise a major component of the biofilm matrix. Many species that are adept at biofilm formation have the capacity to produce multiple types of polysaccharides. Pseudomonas aeruginosa produces at least three extracellular polysaccharides, alginate, Pel and Psl, that have been implicated in biofilm development. Non-mucoid strains can use either Pel or Psl as the primary matrix structural polysaccharide. In this study, we evaluated a range of clin. and environmental P. aeruginosa isolates for their dependence on Pel and Psl for biofilm development. Mutational anal. demonstrates that Psl plays an important role in surface attachment for most isolates. However, there was significant strain-to-strain variability in the contribution of Pel and Psl to mature biofilm structure. This anal. led us to propose four classes of strains based upon their Pel and Psl functional and expression profiles. Our data also suggest that Pel and Psl can serve redundant functions as structural scaffolds in mature biofilms. We propose that redundancy could help preserve the capacity to produce a biofilm when exopolysaccharide genes are subjected to mutation. To test this, we used PAO1, a common lab strain that primarily utilizes Psl in the matrix. As expected, a psl mutant strain initially produced a poor biofilm. After extended cultivation, we demonstrate that this strain acquired mutations that upregulated expression of the Pel polysaccharide, demonstrating the utility of having a redundant scaffold exopolysaccharide. Collectively, our studies revealed both unique and redundant roles for two distinct biofilm exopolysaccharides.
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    109. 109
      Colvin, K. M.; Gordon, V. D.; Murakami, K.; Borlee, B. R.; Wozniak, D. J.; Wong, G. C. L.; Parsek, M. R. The Pel Polysaccharide Can Serve a Structural and Protective Role in the Biofilm Matrix of Pseudomonas Aeruginosa. PLoS Pathog. 2011, 7, e1001264  DOI: 10.1371/journal.ppat.1001264
      109
      The Pel polysaccharide can serve a structural and protective role in the biofilm matrix of Pseudomonas aeruginosa
      Colvin, Kelly M.; Gordon, Vernita D.; Murakami, Keiji; Borlee, Bradley R.; Wozniak, Daniel J.; Wong, Gerard C. L.; Parsek, Matthew R.
      PLoS Pathogens (2011), 7 (1), e1001264CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
      Bacterial extracellular polysaccharides are a key constituent of the extracellular matrix material of biofilms. Pseudomonas aeruginosa is a model organism for biofilm studies and produces three extracellular polysaccharides that have been implicated in biofilm development, alginate, Psl and Pel. Significant work has been conducted on the roles of alginate and Psl in biofilm development, however we know little regarding Pel. In this study, the authors demonstrate that Pel can serve two functions in biofilms. Using a novel assay involving optical tweezers, we demonstrate that Pel is crucial for maintaining cell-to-cell interactions in a PA14 biofilm, serving as a primary structural scaffold for the community. Deletion of pelB resulted in a severe biofilm deficiency. This effect is strain-specific. Loss of Pel prodn. in the lab. strain PAO1 resulted in no difference in attachment or biofilm development; instead Psl proved to be the primary structural polysaccharide for biofilm maturity. Furthermore, the authors demonstrate that Pel plays a second role by enhancing resistance to aminoglycoside antibiotics. This protection occurs only in biofilm populations. Expression of the pel gene cluster and PelF protein levels are enhanced during biofilm growth compared to liq. cultures. Thus, the authors propose that Pel is capable of playing both a structural and a protective role in P. aeruginosa biofilms.
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    110. 110
      Billings, N.; Ramirez Millan, M.; Caldara, M.; Rusconi, R.; Tarasova, Y.; Stocker, R.; Ribbeck, K. The Extracellular Matrix Component Psl Provides Fast-Acting Antibiotic Defense in Pseudomonas Aeruginosa Biofilms. PLoS Pathog. 2013, 9, e1003526  DOI: 10.1371/journal.ppat.1003526
      110
      The extracellular matrix component Psl provides fast-acting antibiotic defense in Pseudomonas aeruginosa biofilms
      Billings, Nicole; Ramirez Millan, Maria; Caldara, Marina; Rusconi, Roberto; Tarasova, Yekaterina; Stocker, Roman; Ribbeck, Katharina
      PLoS Pathogens (2013), 9 (8), e1003526CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
      Bacteria within biofilms secrete and surround themselves with an extracellular matrix, which serves as a first line of defense against antibiotic attack. Polysaccharides constitute major elements of the biofilm matrix and are implied in surface adhesion and biofilm organization, but their contributions to the resistance properties of biofilms remain largely elusive. Using a combination of static and continuous-flow biofilm expts. we show that Psl, one major polysaccharide in the Pseudomonas aeruginosa biofilm matrix, provides a generic first line of defense toward antibiotics with diverse biochem. properties during the initial stages of biofilm development. Furthermore, we show with mixed-strain expts. that antibiotic-sensitive "non-producing" cells lacking Psl can gain tolerance by integrating into Psl-contg. biofilms. However, non-producers dil. the protective capacity of the matrix and hence, excessive incorporation can result in the collapse of resistance of the entire community. Our data also reveal that Psl mediated protection is extendible to E. coli and S. aureus in co-culture biofilms. Together, our study shows that Psl represents a crit. first bottleneck to the antibiotic attack of a biofilm community early in biofilm development.
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    111. 111
      van Tilburg Bernardes, E.; Charron-Mazenod, L.; Reading, D. J.; Reckseidler-Zenteno, S. L.; Lewenza, S. Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2017, 61, e01997-16  DOI: 10.1128/AAC.01997-16
      There is no corresponding record for this reference.
    112. 112
      Cascioferro, S.; Cusimano, M. G.; Schillaci, D. Antiadhesion Agents against Gram-Positive Pathogens. Future Microbiol. 2014, 9, 1209– 1220,  DOI: 10.2217/fmb.14.56
      112
      Antiadhesion agents against Gram-positive pathogens
      Cascioferro, Stella; Cusimano, Maria Grazia; Schillaci, Domenico
      Future Microbiology (2014), 9 (10), 1209-1220CODEN: FMUIAR; ISSN:1746-0913. (Future Medicine Ltd.)
      A review. A fundamental step of Gram-pos. pathogenesis is the bacterial adhesion to the host tissue involving interaction between bacterial surface mols. and host ligands. This review is focused on antivirulence compds. that target Gram-pos. adhesins and on their potential development as therapeutic agents alternative or complementary to conventional antibiotics in the contrast of pathogens. In particular, compds. that target the sortase A, wall theicoic acid inhibitors, carbohydrates able to bind bacterial proteins, and proteins capable of influencing the bacterial adhesion, were described. We further discuss the advantages and disadvantages of this strategy in the development of novel antimicrobials and the future perspective of this research field still at its 1st steps.
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    113. 113
      Berne, C.; Ellison, C. K.; Ducret, A.; Brun, Y. V. Bacterial Adhesion at the Single-Cell Level. Nat. Rev. Microbiol. 2018, 16, 616– 627,  DOI: 10.1038/s41579-018-0057-5
      113
      Bacterial adhesion at the single-cell level
      Berne, Cecile; Ellison, Courtney K.; Ducret, Adrien; Brun, Yves V.
      Nature Reviews Microbiology (2018), 16 (10), 616-627CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
      The formation of multicellular microbial communities, called biofilms, starts from the adhesion of a few planktonic cells to the surface. The transition from a free-living planktonic lifestyle to a sessile, attached state is a multifactorial process that is detd. by biol., chem. and phys. properties of the environment, the surface and the bacterial cell. The initial weak, reversible interactions between a bacterium and a surface strengthen to yield irreversible adhesion. In this Review, we summarize our understanding of the mechanisms governing bacterial adhesion at the single-cell level, including the phys. forces experienced by a cell before reaching the surface, the first contact with a surface and the transition from reversible to permanent adhesion.
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    114. 114
      Terlizzi, M. E.; Gribaudo, G.; Maffei, M. E. UroPathogenic Escherichia Coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-Antibiotic Antimicrobial Strategies. Front. Microbiol. 2017, 8, 1566,  DOI: 10.3389/fmicb.2017.01566
      114
      UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies
      Terlizzi Maria E; Gribaudo Giorgio; Maffei Massimo E
      Frontiers in microbiology (2017), 8 (), 1566 ISSN:1664-302X.
      Urinary tract infections (UTIs) are one of the most common pathological conditions in both community and hospital settings. It has been estimated that about 150 million people worldwide develop UTI each year, with high social costs in terms of hospitalizations and medical expenses. Among the common uropathogens associated to UTIs development, UroPathogenic Escherichia coli (UPEC) is the primary cause. UPEC strains possess a plethora of both structural (as fimbriae, pili, curli, flagella) and secreted (toxins, iron-acquisition systems) virulence factors that contribute to their capacity to cause disease, although the ability to adhere to host epithelial cells in the urinary tract represents the most important determinant of pathogenicity. On the opposite side, the bladder epithelium shows a multifaceted array of host defenses including the urine flow and the secretion of antimicrobial substances, which represent useful tools to counteract bacterial infections. The fascinating and intricate dynamics between these players determine a complex interaction system that needs to be revealed. This review will focus on the most relevant components of UPEC arsenal of pathogenicity together with the major host responses to infection, the current approved treatment and the emergence of resistant UPEC strains, the vaccine strategies, the natural antimicrobial compounds along with innovative anti-adhesive and prophylactic approaches to prevent UTIs.
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    115. 115
      Chorell, E.; Pinkner, J. S.; Phan, G.; Edvinsson, S.; Buelens, F.; Remaut, H.; Waksman, G.; Hultgren, S. J.; Almqvist, F. Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity. J. Med. Chem. 2010, 53, 5690– 5695,  DOI: 10.1021/jm100470t
      115
      Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity
      Chorell, Erik; Pinkner, Jerome S.; Phan, Gilles; Edvinsson, Sofie; Buelens, Floris; Remaut, Han; Waksman, Gabriel; Hultgren, Scott J.; Almqvist, Fredrik
      Journal of Medicinal Chemistry (2010), 53 (15), 5690-5695CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Exptl. evaluation showed that proper substitution of this position affected the biol. activity of the compd. Aryl substituents resulted in pilicides, e.g. I, with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was detd. by X-ray crystallog.
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    116. 116
      Chahales, P.; Hoffman, P. S.; Thanassi, D. G. Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane. Antimicrob. Agents Chemother. 2016, 60, 2028– 2038,  DOI: 10.1128/AAC.02221-15
      116
      Nitazoxanide inhibits pilus biogenesis by interfering with folding of the usher protein in the outer membrane
      Chahales, Peter; Hoffman, Paul S.; Thanassi, David G.
      Antimicrobial Agents and Chemotherapy (2016), 60 (4), 2028-2038CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Many bacterial pathogens assemble surface fibers termed pili or fimbriae that facilitate attachment to host cells and colonization of host tissues. The chaperone/usher (CU) pathway is a conserved secretion system that is responsible for the assembly of virulence- assocd. pili by many different Gram-neg. bacteria. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and an integral outer membrane (OM) assembly and secretion platform termed the usher. Nitazoxanide (NTZ), an antiparasitic drug, was previously shown to inhibit the function of aggregative adherence fimbriae and type 1 pili assembled by the CU pathway in enteroaggregative Escherichia coli, an important causative agent of diarrhea. We show here that NTZ also inhibits the function of type 1 and P pili from uropathogenic E. coli (UPEC). UPEC is the primary causative agent of urinary tract infections, and type 1 and P pili mediate colonization of the bladder and kidneys, resp. By anal. of the different stages of the CU pilus biogenesis pathway, we show that treatment of bacteria with NTZ causes a redn. in the no. of usher mols. in the OM, resulting in a loss of pilus assembly on the bacterial surface. In addn., we det. that NTZ specifically prevents proper folding of the usher β-barrel domain in the OM. Our findings demonstrate that NTZ is a pilicide with a novel mechanism of action and activity against diverse CU pathways. This suggests that further development of the NTZ scaffold may lead to new antivirulence agents that target the usher to prevent pilus assembly.
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    117. 117
      Opperman, T. J.; Nguyen, S. T. Recent Advances toward a Molecular Mechanism of Efflux Pump Inhibition. Front. Microbiol. 2015, 6, 421,  DOI: 10.3389/fmicb.2015.00421
      117
      Recent advances toward a molecular mechanism of efflux pump inhibition
      Opperman Timothy J; Nguyen Son T
      Frontiers in microbiology (2015), 6 (), 421 ISSN:1664-302X.
      Multidrug resistance (MDR) in Gram-negative pathogens, such as the Enterobacteriaceae and Pseudomonas aeruginosa, poses a significant threat to our ability to effectively treat infections caused by these organisms. A major component in the development of the MDR phenotype in Gram-negative bacteria is overexpression of Resistance-Nodulation-Division (RND)-type efflux pumps, which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell. Consequently, bacterial efflux pumps are an important target for developing novel antibacterial treatments. Potent efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. Several potent inhibitors of RND-type efflux pump have been reported in the literature, and at least three of these EPI series were optimized in a pre-clinical development program. However, none of these compounds have been tested in the clinic. One of the major hurdles to the development of EPIs has been the lack of biochemical, computational, and structural methods that could be used to guide rational drug design. Here, we review recent reports that have advanced our understanding of the mechanism of action of several potent EPIs against RND-type pumps.
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    118. 118
      Yilmaz, S.; Altinkanat-Gelmez, G.; Bolelli, K.; Guneser-Merdan, D.; Ufuk Over-Hasdemir, M.; Aki-Yalcin, E.; Yalcin, I. Binding Site Feature Description of 2-Substituted Benzothiazoles as Potential AcrAB-TolC Efflux Pump Inhibitors in E. Coli. SAR QSAR Environ. Res. 2015, 26, 853– 871,  DOI: 10.1080/1062936X.2015.1106581
      118
      Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli
      Yilmaz, S.; Altinkanat-Gelmez, G.; Bolelli, K.; Guneser-Merdan, D.; Ufuk Over-Hasdemir, M.; Aki-Yalcin, E.; Yalcin, I.
      SAR and QSAR in Environmental Research (2015), 26 (10), 853-871CODEN: SQERED; ISSN:1026-776X. (Taylor & Francis Ltd.)
      The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-neg. bacteria. However, although a no. of bacterial RND efflux pump inhibitors have been developed, there has been no clin. available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clin. strain. The results indicated that the BSN compds. did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was obsd. In order to describe the binding site features of these BSN compds. with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calcd. binding energy scores revealed that the tested compds. BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compds. BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compds. are acting as the putative substrates of AcrB.
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    119. 119
      Naaz, F.; Srivastava, R.; Singh, A.; Singh, N.; Verma, R.; Singh, V. K.; Singh, R. K. Molecular Modeling, Synthesis, Antibacterial and Cytotoxicity Evaluation of Sulfonamide Derivatives of Benzimidazole, Indazole, Benzothiazole and Thiazole. Bioorg. Med. Chem. 2018, 26, 3414– 3428,  DOI: 10.1016/j.bmc.2018.05.015
      119
      Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole
      Naaz, Farha; Srivastava, Ritika; Singh, Anuradha; Singh, Nidhi; Verma, Rajesh; Singh, Vishal K.; Singh, Ramendra K.
      Bioorganic & Medicinal Chemistry (2018), 26 (12), 3414-3428CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      A new series of heterocyclic mols. bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broth diln. method, mols. were found to be highly active (MIC value 50-3.1 μg/mL) against different human pathogens, namely B. cereus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was obsd. during detn. of FIC where mols. were used in combination with ref. drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination - varying concn. of test compds. and 1/2 MIC of ref. drugs or varying concn. of ref. drugs and 1/2 MIC of test compds., was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4-32 times more potent than the test mol. The mols. also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results pos. indicated towards the development of lead antibacterials using the combination approach.
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    120. 120
      Abu-Melha, S.; Edrees, M. M.; Salem, H. H.; Kheder, N. A.; Gomha, S. M.; Abdelaziz, M. R. Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents. Molecules 2019, 24, 539,  DOI: 10.3390/molecules24030539
      120
      Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents
      Abu-Melha, Sraa; Edrees, Mastoura M.; Salem, Heba H.; Kheder, Nabila A.; Gomha, Sobhi M.; Abdelaziz, Mohamad R.
      Molecules (2019), 24 (3), 539/1-539/15CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      Two novel series of thiazole-based heterocycles I [R = C(O)Me, CO2Et, C(O)NHPh; Ar = Ph, 4-MeC6H4, 4-ClC6H4, etc.] and II [Ar1 = Ph, 4-MeOC6H4, 4-ClC6H4; Ar2 = Ph, 4-MeC6H4] were synthesized using 1,3-dipolar cycloaddn. reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. Various in vitro biol. assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of compds. I and II. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compds. displayed antitumor activities and compds. I [R = CO2Et; Ar = 2,4-Cl2C6H3] and II [Ar1 = 4-ClC6H4; Ar2 = Ph] showed most potent activity. Compd. I [R = CO2Et; Ar = 4-MeC6H4] most potent activity against S. aureus, B. subtilis and E. coli. Compd I [R = C(O)NHPh; Ar = Ph] exerted the highest antibacterial activity against P. vulgaris.
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    121. 121
      Reddy, N. B.; Zyryanov, G. V.; Reddy, G. M.; Balakrishna, A.; Padmaja, A.; Padmavathi, V.; Reddy, C. S.; Garcia, J. R.; Sravya, G. Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and Pyrazolyl Thiazoles as Potential Antimicrobial Agents. J. Heterocyclic Chem. 2019, 56, 589– 596,  DOI: 10.1002/jhet.3435
      There is no corresponding record for this reference.
    122. 122
      Franchini, C.; Muraglia, M.; Corbo, F.; Florio, M. A.; Di Mola, A.; Rosato, A.; Matucci, R.; Nesi, M.; van Bambeke, F.; Vitali, C. Synthesis and Biological Evaluation of 2-Mercapto-1,3-Benzothiazole Derivatives with Potential Antimicrobial Activity. Arch. Pharm. 2009, 342, 605– 613,  DOI: 10.1002/ardp.200900092
      122
      Synthesis and Biological Evaluation of 2-Mercapto-1,3-benzothiazole Derivatives with Potential Antimicrobial Activity
      Franchini, Carlo; Muraglia, Marilena; Corbo, Filomena; Florio, Marco Antonio; Di Mola, Antonia; Rosato, Antonio; Matucci, Rosanna; Nesi, Marta; van Bambeke, Francoise; Vitali, Cesare
      Archiv der Pharmazie (Weinheim, Germany) (2009), 342 (10), 605-613CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compds. with a potent antimicrobial profile, we designed and synthesized low mol. wt. 2-mercaptobenzothiazole derivs. 2a-2l and 3a-3l. Both series were screened for in-vitro antibacterial activity against the representative panel of Gram-pos. and Gram-neg. bacteria strains. The biol. screening identified compds. 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, resp. The replacement of the S-H by the S-Bn moiety resulted in considerable loss of the antibacterial action of the 3a-3l series. The antibiotic action of compds.2e and 2l was also investigated by testing their activity against some clin. isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our mols. was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compds. by MTS assay against HeLa and MRC-5 cell lines.
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    123. 123
      Cindrić, M.; Perić, M.; Kralj, M.; Martin-Kleiner, I.; David-Cordonnier, M.-H.; Paljetak, H. Č.; Matijašić, M.; Verbanac, D.; Karminski-Zamola, G.; Hranjec, M. Antibacterial and Antiproliferative Activity of Novel 2-Benzimidazolyl- and 2-Benzothiazolyl-Substituted Benzo[b]Thieno-2-Carboxamides. Mol. Diversity 2018, 22, 637– 646,  DOI: 10.1007/s11030-018-9822-7
      123
      Antibacterial and antiproliferative activity of novel 2-benzimidazolyl- and 2-benzothiazolyl-substituted benzo[b]thieno-2-carboxamides
      Cindric, Maja; Peric, Mihaela; Kralj, Marijeta; Martin-Kleiner, Irena; David-Cordonnier, Marie-Helene; Paljetak, Hana Cipcic; Matijasic, Mario; Verbanac, Donatella; Karminski-Zamola, Grace; Hranjec, Marijana
      Molecular Diversity (2018), 22 (3), 637-646CODEN: MODIF4; ISSN:1381-1991. (Springer)
      Novel (nitro/amino)substituted 2-benzimidazolyl and 2-benzothiazolyl benzo[b]thieno-2-carboxamides I and I • HCl [R1 = R2 = H, NH2, NO2; X = NH, S] were designed and synthesized as potential antibacterial agents. The antibacterial activity of these compds. I were evaluated against Gram-pos. (Staphylococcus aureus and Enterococcus faecalis) and Gram-neg. bacteria (Escherichia coli and Moraxella catarrhalis). The most promising antibacterial activity was obsd. for the nitro- and amino-substituted benzimidazole derivs. I [R1 = H; R2 = NH2, NO2; X = NH] and I •Hcl [R1 = H, R2 = NH2, X = NH; R1 = NH2, R2 = H, X = NH] with MICs 2-8 μg/mL. Addnl., compds. with inferior antibacterial activity were further tested for their antiproliferative activity in-vitro against three human cancer cell lines. Amino-substituted benzothiazole hydrochloride salt I [R1 = H, R2 = NH2, X = S] displayed the most pronounced and selective activity against the MCF-7 cell line with an IC50 of 40 nM. Furthermore, DNA binding expts. of selected derivs. indicated that DNA cannot be considered as a primary biol. target for this type of compds.
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    124. 124
      Zha, G.-F.; Leng, J.; Darshini, N.; Shubhavathi, T.; Vivek, H. K.; Asiri, A. M.; Marwani, H. M.; Rakesh, K. P.; Mallesha, N.; Qin, H.-L. Synthesis, SAR and Molecular Docking Studies of Benzo[d]Thiazole-Hydrazones as Potential Antibacterial and Antifungal Agents. Bioorg. Med. Chem. Lett. 2017, 27, 3148– 3155,  DOI: 10.1016/j.bmcl.2017.05.032
      124
      Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents
      Zha, Gao-Feng; Leng, Jing; Darshini, N.; Shubhavathi, T.; Vivek, H. K.; Asiri, Abdullah M.; Marwani, Hadi M.; Rakesh, K. P.; Mallesha, N.; Qin, Hua-Li
      Bioorganic & Medicinal Chemistry Letters (2017), 27 (14), 3148-3155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A series of new benzo[d]thiazole-hydrazones analogs were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compds. 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the ref. drug chloramphenicol and rifampicin. Compds. 5, 9, 10, 11, 12, 28 and 30 were good antifungal activity compared to the std. drug ketoconazole. A preliminary study of the structure-activity relation (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the Ph ring. The electron donating (OH and OCH3) groups presented in the analogs, increase the antibacterial activity (except compd. 12), interestingly, while the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compd. 19 and 20). In addn., analogs contg. thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliph. analogs (24-26) shown no activities in both bacterial and fungal stains even in high concns. (100 μg/mL). Mol. docking studies were performed for all the synthesized compds. of which compds. 11, 19 and 20 showed the highest glide G-score.
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    125. 125
      Stenger-Smith, J.; Chakraborty, I.; Mascharak, P. K. Cationic Au(I) Complexes with Aryl-Benzothiazoles and Their Antibacterial Activity. J. Inorg. Biochem. 2018, 185, 80– 85,  DOI: 10.1016/j.jinorgbio.2018.05.003
      125
      Cationic Au(I) complexes with aryl-benzothiazoles and their antibacterial activity
      Stenger-Smith, Jenny; Chakraborty, Indranil; Mascharak, Pradip K.
      Journal of Inorganic Biochemistry (2018), 185 (), 80-85CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      Two cationic Au(I) complexes derived from aryl-benzothiazoles, namely [(PPh3)Au(pbt)](OTf) (1) and [(PPh3)Au(qbt)](OTf) (2) (where pbt=2-(pyridyl)benzothiazole and qbt=(quinolyl)benzothiazole, and OTf-=trifluoromethanesulfonate anion), have been synthesized and structurally characterized by X-ray crystallog. Both complexes exhibit strong antibacterial effects against Gram-neg. bacteria such as Acinetobacter baumannii and Pseudomonas Aeruginosa. Results of examn. of the reactions of 1 and 2 indicate that these cationic Au(I) complexes rapidly cross the bacterial membrane and exert drug action by disrupting cellular function(s) through binding of cytosolic thiol-contg. peptides (such as glutathione) and proteins to the highly reactive (PPh3)Au+ intermediate formed upon in situ dissocn. of pbt or qbt.
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    126. 126
      Maddili, S. K.; Katla, R.; Kannekanti, V. K.; Bejjanki, N. K.; Tuniki, B.; Zhou, C.-H.; Gandham, H. Molecular Interaction of Novel Benzothiazolyl Triazolium Analogues with Calf Thymus DNA and HSA-Their Biological Investigation as Potent Antimicrobial Agents. Eur. J. Med. Chem. 2018, 150, 228– 247,  DOI: 10.1016/j.ejmech.2018.02.056
      126
      Molecular interaction of novel benzothiazolyl triazolium analogues with calf thymus DNA and HSA-their biological investigation as potent antimicrobial agents
      Maddili, Swetha K.; Katla, Ramesh; Kannekanti, Vijaya Kumar; Bejjanki, Naveen Kumar; Tuniki, Balaraju; Zhou, Cheng-He; Gandham, Himabindu
      European Journal of Medicinal Chemistry (2018), 150 (), 228-247CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      The binding behavior between calf thymus DNA and synthesized benzothiazolyl triazolium derivs. as potent antimicrobial agents was explored by spectroscopic applications together with mol. docking study at the sub-domain IIA, binding site I of human serum albumin (HSA). Most of the synthesized derivs. presented significant antimicrobial inhibition when compared with the clin. Norfloxacin, Chloromycin, and Fluconazole. In particular, compd. 5q (2-phenyl-3-(((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-7-ethoxybenzo[d]imidazo[2,1-b]thiazole) presented efficient anti-Bacillus subtilis, anti-Escherichia coli, anti-Salmonella typhi, and anti-Pseudomonas aeruginosa activity with low MIC values of 2-8 μg/mL which were relatively superior to the ref. drugs. The preliminarily investigation of interaction studies with calf thymus DNA demonstrated that the most active compd. 5q could effectively intercalate into DNA to form 5q-DNA complex. Further investigations revealed that human serum albumin could effectively transport compd. 5q while mol. modeling studies with good docking score showed that hydrophobic interactions as well as hydrogen bonds played a significant role in the interaction of compd. 5q with HSA. In addn., the cytotoxic investigation carried out on four different cancerous cell lines (3 human cell lines and 1 murine cell lines) by MTT assay presented that compd. 5n (2-phenyl-3-(((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-7-ethoxybenzo[d]imidazo[2,1-b]thiazole) is active against MDA cell lines with IC50 values less than 100 μg/mL.
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    127. 127
      Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, C.; Soković, M.; Cirić, A.; Glamoclija, J. Novel 4-Thiazolidinone Derivatives as Potential Antifungal and Antibacterial Drugs. Bioorg. Med. Chem. 2010, 18, 426– 432,  DOI: 10.1016/j.bmc.2009.10.041
      127
      Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs
      Omar, Kouatli; Geronikaki, Athina; Zoumpoulakis, Panagiotis; Camoutsis, Charalabos; Sokovic, Marina; Ciric, Ana; Glamoclija, Jasmina
      Bioorganic & Medicinal Chemistry (2010), 18 (1), 426-432CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      As part of ongoing studies in developing new antimicrobials, a class of structurally novel 4-thiazolidinone derivs. incorporating three known bioactive nuclei such as thiazole, thiazolidinone and adamantane was synthesized by the multi-step reaction protocol, already reported in the literature. NMR and Mol. Modeling techniques were employed for structure elucidation and Z/E potential isomerism configuration of the analogs. Evaluation of antibacterial and antifungal activity showed that almost all compds. exhibited better results than ref. drugs thus they could be promising candidates for novel drugs.
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    128. 128
      Deep, A.; Jain, S.; Sharma, P. C.; Mittal, S. K.; Phogat, P.; Malhotra, M. Synthesis, Characterization and Antimicrobial Evaluation of 2,5-Disubstituted-4-Thiazolidinone Derivatives. Arabian J. Chem. 2014, 7, 287– 291,  DOI: 10.1016/j.arabjc.2010.10.032
      128
      Synthesis, characterization and antimicrobial evaluation of 2,5-disubstituted-4-thiazolidinone derivatives
      Deep, Aakash; Jain, Sandeep; Sharma, Prabodh Chander; Mittal, Sanjeev K.; Phogat, Priyanka; Malhotra, Manav
      Arabian Journal of Chemistry (2014), 7 (3), 287-291CODEN: AJCRDR; ISSN:1878-5352. (Elsevier B.V.)
      In the present study novel derivs. of 4-thiazolidinone I (Ar = C6H5, 3-BrC6H4, 4-FC6H4; Ar1 = C6H5, 3-O2NC6H4, 4-ClC6H4, 4-CH3OC6H4) were prepd. from biphenyl-4-carboxylic acid and evaluated for their in vitro antimicrobial activity against two gram neg. strains (Escherichia coli and Pseudomonas aeruginosa) and two gram pos. strains (Bacillus subtilis and Staphylococcus aureus) and fungal strains (Candida albicans and Aspergillus niger). The results revealed that all synthesized compds. have significant biol. activity against the tested microorganisms. Among the synthesized derivs. I (Ar = 3-BrC6H4, Ar1 = 3-O2NC6H4; Ar = Ar1 = 3-BrC6H4) were found to be most effective antimicrobial compds.
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    129. 129
      Angapelly, S.; Sri Ramya, P. V.; SunithaRani, R.; Kumar, C. G.; Kamal, A.; Arifuddin, M. Ultrasound Assisted, VOSO4 Catalyzed Synthesis of 4-Thiazolidinones: Antimicrobial Evaluation of Indazole-4-Thiazolidinone Derivatives. Tetrahedron Lett. 2017, 58, 4632– 4637,  DOI: 10.1016/j.tetlet.2017.10.070
      129
      Ultrasound assisted, VOSO4 catalyzed synthesis of 4-thiazolidinones: Antimicrobial evaluation of indazole-4-thiazolidinone derivatives
      Angapelly, Srinivas; Sri Ramya, P. V.; SunithaRani, Routhu; Kumar, C. Ganesh; Kamal, Ahmed; Arifuddin, Mohammed
      Tetrahedron Letters (2017), 58 (49), 4632-4637CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A simple and expedient multicomponent protocol was developed to synthesize 4-thiazolidinones I (R1 = R5 = R6 = R8 = H, R2 = R3 = R4 = R7 = OCH3; R1 = R2 = R3 = R4 = R5 = R6 = R8 = H, R7 = CF3; R1 = R3 = OCH3, R2 = R4 = R5 = R6 = R8 = H, R7 = F, etc.) by employing VOSO4 as a catalyst under ultrasonic irradn. The significant features of this protocol includes shorter reaction time, high yields, and low catalyst loading, and also the catalyst can be recovered and reused up to next four cycles without significant loss in catalytic activity. All the synthesized novel indazole compds. II (R = 3,4,5-(CH3O)3C6H2, thiophen-2-yl, benzothiazole-2-yl, etc.) were evaluated for their antibacterial and anti-biofilm activities. Compds. II (R = 4-F3CC6H4, 3-F3CC6H4, 4-F3COC6H4) showed promising activity (MIC value of 3.9μg/mL) against K. planticola (MTCC 530). They also exhibited significant bactericidal activity against K. planticola (MTCC 530) (MBC value of 15.6μg/mL). Addnl., II (R = 4-F3CC6H4, 3-F3CC6H4, 4-CF3OC6H4) inhibits biofilm formation (IC50 values ranging between 20.28-20.79μg/mL) in this organism.
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    130. 130
      Pitta, E.; Tsolaki, E.; Geronikaki, A.; Petrović, J.; Glamočlija, J.; Soković, M.; Crespan, E.; Maga, G.; Bhunia, S. S.; Saxena, A. K. 4-Thiazolidinone Derivatives as Potent Antimicrobial Agents: Microwave-Assisted Synthesis, Biological Evaluation and Docking Studies. MedChemComm 2015, 6, 319– 326,  DOI: 10.1039/C4MD00399C
      130
      4-Thiazolidinone derivatives as potent antimicrobial agents: microwave-assisted synthesis, biological evaluation and docking studies
      Pitta, Eleni; Tsolaki, Evangelia; Geronikaki, Athina; Petrovic, Jovana; Glamoclija, Jasmina; Sokovic, Marina; Crespan, Emmanuele; Maga, Giovanni; Bhunia, Shome S.; Saxena, Anil K.
      MedChemComm (2015), 6 (2), 319-326CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      As a part of the authors' ongoing research in the development of new antimicrobials, herein, the authors report the synthesis of ten compds. which combine three bioactive moieties: thiazole, adamantane and 4-thiazolidinone. Evaluation of their antibacterial activity revealed that the newly synthesized compds. exhibited remarkable growth inhibition of a wide spectrum of Gram-pos. bacteria, Gram-neg. bacteria and fungi. The majority of the compds. displayed greater antibacterial activity than the ref. drugs (ampicillin and streptomycin), while the antifungal activity was significantly higher than that of the ref. drugs bifonazole and ketoconazole. Addnl., the title compds. were screened for HIV-1 reverse transcriptase inhibitory activity, showing no significant activity. Moreover, docking studies were performed to explore possible binding modes at the MurB protein of S. aureus.
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    131. 131
      Ahmed, S.; Zayed, M. F.; El-Messery, S. M.; Al-Agamy, M. H.; Abdel-Rahman, H. M. Design, Synthesis, Antimicrobial Evaluation and Molecular Modeling Study of 1,2,4-Triazole-Based 4-Thiazolidinones. Molecules 2016, 21, 568,  DOI: 10.3390/molecules21050568
      131
      Design, synthesis, antimicrobial evaluation and molecular modeling study of 1,2,4-triazole-based 4-thiazolidinones
      Ahmed, Sahar; Zayed, Mohamed F.; El-Messery, Shahenda M.; Al-Agamy, Mohamed H.; Abdel-Rahman, Hamdy M.
      Molecules (2016), 21 (5), 568/1-568/17CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivs. I [R = 3-Cl, 4-OMe; R1 = 4-Me, 4-OMe, 4-NO2, 4-F, 4-Cl] was designed and synthesized via reaction of 5-phenyl-3-(benzylideneamino)-2H-1,2,4-triazoles with mercaptoacetic acid. The newly synthesized compds. I were evaluated for their antibacterial and antifungal activities. Among the tested compds., compd. I [R = 4-OMe; R1 = 4-Cl] showed the highest activity against all the tested strains, except P. vulgaris, with MIC 8 μg/mL and 4 μg/mL against S. aureus and C. albicans, resp. Furthermore, Compds. I [R = 3-Cl, R1 = 4-Cl; R = 4-OMe, R1 = 4-Cl; R = 4-OMe, R1 = 4-NO2] demonstrated moderate anti-mycobacterium activity. The binding mode of the synthesized thiazolidinones to bacterial MurB enzyme was also studied. Good interactions between the docked compds. to the MurB active site were obsd. primarily with Asn83, Arg310, Arg188 and Ser82 amino acid residues.
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    132. 132
      Deep, A.; Narasimhan, B.; Lim, S. M.; Ramasamy, K.; Mishra, R. K.; Mani, V. 4-Thiazolidinone Derivatives: Synthesis, Antimicrobial, Anticancer Evaluation and QSAR Studies. RSC Adv. 2016, 6, 109485– 109494,  DOI: 10.1039/C6RA23006G
      132
      4-Thiazolidinone derivatives: synthesis, antimicrobial, anticancer evaluation and QSAR studies
      Deep, Aakash; Narasimhan, Balasubrmanian; Lim, Siong Meng; Ramasamy, Kalavathy; Mishra, Rakesh Kumar; Mani, Vasudevan
      RSC Advances (2016), 6 (111), 109485-109494CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A series of 4-thiazolidinone derivs. (1-18) was synthesized and tested in vitro for its antimicrobial and anticancer potential. Synthesized compds. were found to be 5 more potent antimicrobial agents than anticancer agents. Anticancer screening results indicated that compd. 13 (IC50 = 15.18 μM) was the most active anticancer agent and was more potent than the std. drug, carboplatin (IC50 > 100 μM). Antimicrobial activity results indicated that 14 was the most active antimicrobial agent (pMICec = 2.14 μM) and may serve as an important lead for the discovery of novel antimicrobial agents. The QSAR studies indicated that the antibacterial and antifungal activities of the synthesized derivs. against different microbial strains were governed by lipophilic parameter, log P, topol. parameter, κα3 and electronic parameters cos E and Nu.E.
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    133. 133
      El-Sayed, E. H.; Fadda, A. A. Synthesis and Antimicrobial Activity of Some Novel Bis Polyfunctional Pyridine, Pyran, and Thiazole Derivatives. J. Heterocyclic Chem. 2018, 55, 2251– 2260,  DOI: 10.1002/jhet.3276
      133
      Synthesis and Antimicrobial Activity of Some Novel bis Polyfunctional Pyridine, Pyran, and Thiazole Derivatives
      El-Sayed, Elsherbiny H.; Fadda, Ahmed A.
      Journal of Heterocyclic Chemistry (2018), 55 (10), 2251-2260CODEN: JHTCAD; ISSN:1943-5193. (Wiley-Blackwell)
      In continuation of efforts to find a new class of antimicrobial agents, treatment of N,N'-(1,4-phenylene)bis(2-cyanoacetamide) I with formaldehyde and either benzoylacetonitrile or malononitrile to afford pyridine derivs., II and III resp. Similarly, treatment of I with different types of aldehydes afforded benzylidene derivs., followed by the reaction with malononitrile dimer to give polyfunctional pyridine deriv. Moreover, cyanoacetamide was reacted with chalcone, benzylidenemalononitrile, and 1,3-diketone to afford pyran derivs. resp., followed by the reaction with ammonium acetate to afford polyfunctional pyridine derivs., resp. Furthermore, thiazole deriv. was prepd. via treatment of I with elemental sulfur and Ph isothiocyanate. The newly synthesized compds. were evaluated as antimicrobial activities.
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    134. 134
      Devine, S. M.; Mulcair, M. D.; Debono, C. O.; Leung, E. W. W.; Nissink, J. W. M.; Lim, S. S.; Chandrashekaran, I. R.; Vazirani, M.; Mohanty, B.; Simpson, J. S.; Baell, J. B.; Scammells, P. J.; Norton, R. S.; Scanlon, M. J. Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold. J. Med. Chem. 2015, 58, 1205– 1214,  DOI: 10.1021/jm501402x
      134
      Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold
      Devine, Shane M.; Mulcair, Mark D.; Debono, Cael O.; Leung, Eleanor W. W.; Nissink, J. Willem M.; Lim, San Sui; Chandrashekaran, Indu R.; Vazirani, Mansha; Mohanty, Biswaranjan; Simpson, Jamie S.; Baell, Jonathan B.; Scammells, Peter J.; Norton, Raymond S.; Scanlon, Martin J.
      Journal of Medicinal Chemistry (2015), 58 (3), 1205-1214CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      We have identified a class of mols., known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophys. binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compd. libraries used for high-throughput screening (HTS). This anal. revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties assocd. with optimizing them into a lead compd. makes them, in our opinion, poor scaffolds for fragment libraries.
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    135. 135
      Baell, J. B.; Nissink, J. W. M. Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017—Utility and Limitations. ACS Chem. Biol. 2018, 13, 36– 44,  DOI: 10.1021/acschembio.7b00903
      135
      Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations
      Baell, Jonathan B.; Nissink, J. Willem M.
      ACS Chemical Biology (2018), 13 (1), 36-44CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      A review on all necessary considerations for the appropriate use of PAINs filters formulated to process hundreds and thousands of compds. in seconds, and identify PAINS in order to exclude them from further anal.
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    136. 136
      Baell, J. B.; Holloway, G. A. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. J. Med. Chem. 2010, 53, 2719– 2740,  DOI: 10.1021/jm901137j
      136
      New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
      Baell, Jonathan B.; Holloway, Georgina A.
      Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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    137. 137
      Dahlin, J. L.; Nissink, J. W. M.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.; Zhang, Z.; Walters, M. A. PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS. J. Med. Chem. 2015, 58, 2091– 2113,  DOI: 10.1021/jm5019093
      137
      PAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTS
      Dahlin, Jayme L.; Nissink, J. Willem M.; Strasser, Jessica M.; Francis, Subhashree; Higgins, LeeAnn; Zhou, Hui; Zhang, Zhiguo; Walters, Michael A.
      Journal of Medicinal Chemistry (2015), 58 (5), 2091-2113CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compds., while understanding the chem. basis for these adverse behaviors often goes unexplored in pursuit of lead compds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compds. Herein, we characterize the chem. basis for assay interference and promiscuous enzymic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compds. (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compds. react covalently with cysteines on multiple proteins. Unfortunately, compds. contg. these chemotypes have been published as screening actives in reputable journals and even touted as chem. probes or preclin. candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compds., guide screening library design, and prevent follow-up on undesirable chem. matter.
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    138. 138
      Forman, H. J.; Davies, K. J. A.; Ursini, F. How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis versus Free Radical Scavenging in Vivo. Free Radical Biol. Med. 2014, 66, 24– 35,  DOI: 10.1016/j.freeradbiomed.2013.05.045
      138
      How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo
      Forman, Henry J.; Davies, Kelvin J. A.; Ursini, Fulvio
      Free Radical Biology & Medicine (2014), 66 (), 24-35CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      A review. We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiol. evidence for disease prevention by dietary antioxidants and chem. evidence that such compds. react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para-hormesis," provides a means for regulating physiol. nontoxic concns. of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health.
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    139. 139
      Kaminskyy, D.; Kryshchyshyn, A.; Lesyk, R. 5-Ene-4-Thiazolidinones - An Efficient Tool in Medicinal Chemistry. Eur. J. Med. Chem. 2017, 140, 542– 594,  DOI: 10.1016/j.ejmech.2017.09.031
      139
      5-Ene-4-thiazolidinones - An efficient tool in medicinal chemistry
      Kaminskyy, Danylo; Kryshchyshyn, Anna; Lesyk, Roman
      European Journal of Medicinal Chemistry (2017), 140 (), 542-594CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. The presented review is an attempt to summarize a huge vol. of data on 5-ene-4-thiazolidinones being a widely studied class of small mols. used in modern org. and medicinal chem. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivs., modification of the C5 position of the basic core and synthesis of the target compds. in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacol. profiles of 5-ene derivs. of different 4-thiazolidinone subtypes belonging to hit-, lead-compds., drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compds. (esp. 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compds. (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacol. effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: (i) complication of the fragment in the C5 position; (ii) introduction of the substituents in the N3 position (esp. fragments with carboxylic group or its derivs.); (iii) annealing in complex heterocyclic systems; (iv) combination with other pharmacol. attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compds. with potent pharmacol. application is described. The chem. transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.
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