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Article

Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking

by
Dasharath Kondhare
1,
Sushma Deshmukh
1 and
Harshad Lade
2,*
1
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431606, Maharashtra, India
2
Department of Environmental Engineering, Konkuk University, Seoul 05029, Korea
*
Author to whom correspondence should be addressed.
Processes 2019, 7(7), 417; https://doi.org/10.3390/pr7070417
Submission received: 30 May 2019 / Revised: 24 June 2019 / Accepted: 25 June 2019 / Published: 2 July 2019
(This article belongs to the Special Issue Extraction, Characterization and Pharmacology of Natural Products)
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Abstract

:
Curcumin, a constituent of Curcuma longa, has shown numerous biological and pharmacological activities, including antidiabetic effects. Here, a novel series of curcumin analogues were synthesized and evaluated for in vitro inhibition of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which plays a key role in the onset and progression of diabetic complications. Biological activity studies showed that all the curcuminoids exhibited moderate to good AR inhibitory (ARI) activities compared with that of the quercetin standard. Importantly, compounds 8d, 8h, 9c, 9e, and 10g demonstrated promising ARI activities, with the 50% inhibitory concentration (IC50) values of 5.73, 5.95, 5.11, 5.78, and 5.10 µM, respectively. Four other compounds exhibited IC50 values in the range of 6.04–6.18 µM. Methyl and methoxy derivatives showed a remarkable ARI potential compared with that of other substitutions on the aromatic ring. Molecular docking experiments demonstrated that the most active curcuminoid (10g) was able to favorably bind in the active site of the AR enzyme. The potent ARI activities exhibited by the curcuminoids were attributed to their substitution patterns on the aromatic moiety, which may provide novel leads in the development of therapeutics for the treatment of diabetic complications.

1. Introduction

Diabetes mellitus (DM) is a complex metabolic disorder characterized by high blood glucose levels and the development of chronic complications, including neuropathy, nephropathy, retinopathy, and cataracts [1,2]. This disorder also leads to kidney failure, heart attack, and stroke, which results in more than 50% of fatalities in diabetic patients [3,4]. The International Diabetes Federation (IDF) has reported that an estimated 425 million adults worldwide had DM in 2017, and predicted that almost 642 million people will have diabetes by 2040 [5]. According to the IDF report, 10 countries, including three Asian countries (Indonesia, India, and Japan), will have the largest populations of diabetes patients by 2035 and will be the center of the DM epidemic [6]. Several lines of evidence have proven that DM is prone to chronic complications, and those are the major threat to diabetic patients [7].
Recent advances in the understanding of DM pathology have revealed that the aldose reductase (AR; alditol:(nicotinamide adenine dinucleotide phosphate (NADP+) 1-oxidoreductase, EC 1.1.1.21) enzyme activity is mainly responsible for the induction of diabetic complications. The enzyme AR is comprised of a single polypeptide chain with 315 residues. It is the first and rate-limiting enzyme in the polyol pathway of glucose metabolism, which catalyzes the reduction of glucose to sorbitol, later oxidized to fructose by sorbitol dehydrogenase, with NAD+ as a cofactor [4]. The substrate-binding site is in a large, deep elliptical pocket with the nicotinamide ring of aldose (NADPH) cofactor in the bottom. Even though the catalytic mechanism of AR has not yet been determined, the crystal structures reveal the active role of Tyr 48, His 110, and the nicotinamide ring in the catalytic reactions. Therefore, the inhibition of AR, which can prevent the accumulation of sorbitol, has been considered a promising therapeutic strategy for designing drugs able to delay and prevent diabetic complications.
Up to now, a wide variety of AR inhibitors, both derived from natural products and chemically synthesized, have been identified and evaluated in preclinical and clinical trials [8,9,10]. However, efforts to commercialize these inhibitors have been unsuccessful, as most of them were found to be clinically inadequate, owing to pharmacokinetic drawbacks, adverse side effects, or low in vivo efficacies [9,11]. Currently, epalrestat is the only commercially available AR inhibitory (ARI) drug, approved only in India and Japan, for the management of DM [12], but it still has some drawbacks [13,14].
Various AR inhibitors from different chemical classes appear to have certain electronic and steric characteristics in common; in particular, essential requisites for the enzyme inhibitory activity seem to be a planar structure with two hydrophobic moieties (aromatic groups) and the presence of an acidic proton, as carboxylic acid and the cyclic imide are supposed to interact with the cationic site of AR in their dissociated anionic forms [8]. Hence, the structural characteristics of phenolic compounds such as curcumin inspired us to synthesize its analogs as lead compounds containing some modifications in a number of carbons in conjugation, together with the introduction of different substitutions on aromatic groups.
It has previously been shown that curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione], a diphenolic constituent found in the rhizome of the herb Curcuma longa (commonly known as turmeric), possesses multiple pharmaceutical properties, accounting for various medicinal applications, including anticarcinogenic [15,16], anti-human immunodeficiency virus (HIV)-1 [17], antibiofilm formation [18,19], anti-inflammatory [20], anti-Alzheimer’s [21], anti-angiogenic [22], antimicrobial [23], antiviral [24], antimutagenic [25], antioxidant [26], and antidiabetic activities [27]. Curcumin has attracted potential therapeutic interest because it has no side effects and acts on a number of biological targets [28,29]. The therapeutic benefits of curcumin appear to be mainly attributable to the enolic ketone as a functional group [30] and to the presence of active methylene hydrogen [31]. However, the application of curcumin in medicine is often limited by its low bioavailability, poor aqueous solubility, and rapid metabolism [19,32]. Therefore, to overcome the limitations of the natural product curcumin and to develop potent antidiabetic agents, a series of curcumin analogs, which share similar structural features while displaying equal or better efficacies than that of curcumin, was synthesized with extended conjugation (Figure 1). As depicted in Figure 1, curcuminoids contain an extra C­–C double bond and without the moiety containing active methylene (–CH2–) and carbonyl (C=O) groups of curcumin. Hence, a chemically diverse series of molecules with a probable new mechanism of action was synthesized and evaluated for their ARI activity. The synthesis of curcuminoids was carried out by condensation of acetone and a substituted benzaldehyde or cinnamaldehyde in a base-catalyzed Claisen–Schmidt reaction. All synthesized curcuminoids were evaluated for their in vitro inhibition of an AR enzyme isolated from bovine lenses. The biological activities of the curcuminoids were further substantiated by the results of molecular docking studies.

2. Materials and Methods

2.1. Chemistry

All starting materials and reagents were purchased from Sigma–Aldrich (St. Louis, MO, USA) and used as received. NADPH, Diethylaminoethyl (DEAE)-cellulose, DL-glyceraldehyde, ethylenediaminetetraacetic acid, and Folin–Ciocalteu’s phenol reagent were procured from HiMedia Laboratories Pvt. Ltd. (Mumbai, India). Melting points of the synthesized compounds were recorded in open glass capillaries using an electrical melting point apparatus and were not corrected; 1H nuclear magnetic resonance (NMR) spectra were recorded on a Mercury-VX 400 MHz NMR spectrometer (Varian, UK) at room temperature. Infrared (IR) spectra were obtained on a Nicolet iS 10 spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) using KBr discs. Mass spectral analysis was performed on an Agilent mass spectrometer (Agilent Technology, Palo Alto, CA, USA) operated at an ionization potential of 70 eV. Reactions were monitored by thin-layer chromatography on silica gel 60 F254 plates (Merck, Darmstadt, Germany).

2.2. Synthesis of Curcumin Analogues

The compounds described in this study were synthesized by a straightforward chemistry according to Claisen–Schmidt condensation (Figure 2). Briefly, aldehyde (11 or 13, 2 mmol and 13, 1 mmol) was added dropwise to a stirred solution of sodium hydroxide (1 N, 1 mL) and distilled ethanol (5 mL), and the resulting reaction mixture was stirred at the ice-cold temperature for 15 min. Then, an appropriate ketone (12 or 14, 1 mmol) was added dropwise with vigorous stirring, and the reaction mixture was allowed to stir at room temperature. After completion of the starting material, the reaction mixture was quenched by cold water (10 mL) and further stirred for 10 min at room temperature. The separated solid product was filtered, washed with cold water several times, and dried under a high vacuum. The solid was recrystallized with ethanol to afford a pure compound with a moderate to excellent yield.

2.3. Characterization of the Compounds Was Carried out Using Their Melting Point (mp), IR, 1H NMR, and Mass Spectral Data as Follows

(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one (8a). Pale yellow solid; mp 110–112 °C. IR (KBr, cm−1): 3025, 2941, 2932, 2848, 1650, 1622, 1613, 1535, 1460, 1363, 1220, 1120, 1063, 923, 835, 736. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 15.9 Hz, 2H), 7.61 (m, 4H), 7.42 (m, 6H), 7.11 (d, J = 15.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 188.4, 143.1, 134.5, 130.6, 129.2, 128.3, 125.1. EI MS: m/z (rel. abund. %) = M+1 235 (M+, 100%). Anal. calcd. (%) for C17H14O (234.10): C, 87.15; H, 6.02. Found: C, 87.18; H, 6.05.
(1E,4E)-1,5-bis(3,4,5-trimethoxyphenyl)penta-1,4-dien-3-one (8b). Pale yellow solid; mp 123–124 °C. IR (KBr, cm−1): 3024, 2971, 2922, 2865, 2820, 1653, 1623, 1580, 1452, 1361, 1205, 1092, 962, 748, 689. 1H NMR (400 MHz, CDCl3) δ7.65 (d, J = 15.9 Hz, 2H), 6.95 (d, J = 15.9 Hz, 2H), 6.82 (s, 2H), 3.93–3.95 (s, 18H). 13C NMR (100 MHz, CDCl3) δ 175.2, 154.5, 142.4, 131.4, 125.6, 106.7, 61.1, 56.3. EI MS: m/z (rel. abund. %) = M+1 415. Anal. calcd. (%) for C23H26O7 (414.17): C, 66.65; H, 6.32. Found: C, 66.63; H, 6.30.
(1E,4E)-1,5-bis(4-bromophenyl)penta-1,4-dien-3-one (8c). Yellow solid; mp 211–213 °C. IR (KBr, cm−1): 3121, 2975, 2969, 2982, 2862, 2842, 1652, 1620, 1575, 1455, 1362, 1242, 1189, 955, 747, 697. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 15.9 Hz, 2H), 7.54 (d, J = 8.5 Hz, 4H), 7.45 (d, J = 8.5 Hz, 4H), 7.05 (d, J = 15.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 143.2, 140.3, 134.2, 133.4, 130.2, 126.1. EI MS: m/z (rel. abund. %) = M+1 391. Anal. calcd. (%) for C17H12Br2O (389.93): C, 52.08; H, 3.08. Found: C, 52.10; H, 3.04.
(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one (8d). Yellow solid; mp 134–136 °C. IR (KBr, cm−1): 3327, 3125, 3067, 2975, 2932, 2846, 2810, 1648, 1628, 1571, 1466, 1363, 1205, 1180, 960, 742, 690. 1HNMR (400 MHz, CDCl3) δ 8.05 (d, J = 16.2 Hz, 2H), 7.25 (dd, J = 8.3, 0.8 Hz, 2H), 7.15 (d, J = 16.2 Hz, 2H), 7.10 (t, J = 8.1 Hz, 2H), 6.95 (dd, J = 8.3, 0.8 Hz, 2H), 3.92 (s, 6H), 3.86 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 190.1, 154.3, 149.1, 138.8, 130.2, 127.3, 124.1, 120.1, 114.3, 62.1, 56.1. EI MS: m/z (rel. abund. %) = M+1 355. Anal. calcd. (%) for C21H22O5 (354.15): C, 71.17; H, 6.26. Found: C, 71.15; H, 6.25.
(1E,4E)-1,5-bis(4-chlorophenyl)penta-1,4-dien-3-one (8e). Pale yellow solid; mp 184–186 °C. IR (KBr, cm−1): 3241, 3125, 3086, 2978, 2952, 2927, 2861, 2822, 1652, 1620, 1580, 1450, 1348, 1214, 1090, 964, 742, 693. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 16.2 Hz, 2H), 7.25 (dd, J = 8.3, 0.8 Hz, 2H), 7.16 (d, J = 16.2 Hz, 2H), 7.10 (t, J = 8.1 Hz, 2H), 6.95 (dd, J = 8.3, 0.8 Hz, 2H), 3.92 (s, 6H), 3.90 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 191.4, 154.6, 149.2, 138.7, 130.3, 127.4, 125.5, 120.1, 115.2, 62.5, 56.1. EI MS: m/z (rel. abund. %) = M+1 303. Anal. calcd. (%) for C17H12Cl2O (302.03): C, 67.35; H, 3.99. Found: C, 67.33; H, 4.02.
(1E,4E)-1,5-bis(3-nitrophenyl)penta-1,4-dien-3-one (8f). Yellow solid; IR (KBr, cm−1): 3148, 3021, 2975, 2965, 2925, 2865, 2865, 1659, 1658, 1580.3, 1455, 1362, 1275, 1095, 945, 737, 691. 1H NMR (400 MHz, CDCl3) δ8.52 (s, 2H), 8.24 (d, J = 7.3 Hz, 2H), 7.92 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 16.1 Hz, 2H), 7.64 (dd, J = 7.9, 7.9 Hz, 2H), 7.21 (d, J = 16.1 Hz, 2H). EI MS: m/z (rel. abund. %) = M+1 325; Anal. calcd. (%) for C17H12N2O5 (324.07): C, 62.96; H, 3.73; N, 8.64. Found: C, 62.95; H, 3.71; N, 8.65.
(1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one (8g). Pale yellow solid; IR (KBr, cm−1): 3168, 3066, 2975, 2937, 2865, 2818, 1652, 1620, 1576, 1452, 1365, 1263, 1169, 935, 741, 690. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 15.9 Hz, 2H), 7.06 (d, J = 15.9 Hz, 2H), 6.62 (d, J = 2.2 Hz, 4H), 6.35 (t, J = 2.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 190.9, 161.2, 146.3, 138.6, 127.9, 108.1, 104.6. EI MS: m/z (rel. abund. %) = M+1 371; M+1 = 372. Anal. calcd. (%) for C17H10Cl4O (369.95): C, 54.88; H, 2.71. Found: C, 54.86; H, 2.69.
(1E,4E)-1,5-bis-(4-methoxyphenyl)penta-1,4-dien-3-one (8h). Pale yellow solid; mp 130–132 °C. IR (KBr, cm−1): 3241.4, 3162.8, 3027.3, 2978.3, 2932.5, 2862.6, 2838.4, 1654.8, 1648.8, 1578.1, 1465.6, 1363.6, 1272.2, 1075.4, 961.8, 742.4, 691.2. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 15.7 Hz, 2H), 7.57 (d, J = 8.5 Hz, 4H), 6.94 (d, J = 15.7 Hz, 2H), 6.91 (d, J = 8.5 Hz, 4H), 3.84 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 187.8, 162.1, 143.7, 131.2, 126.9, 124.1, 115.1, 55.8. EI MS: m/z (rel. abund. %) = M+1 295. Anal. calcd. (%) for C19H18O3 (294.13): C, 77.53; H, 6.16. Found: C, 77.55; H, 6.14.
(1E,4E)-1,5-di(naphthalen-2-yl)penta-1,4-dien-3-one (8i). Yellow solid; mp 244–246 °C. IR (KBr, cm−1): 3346.4, 3265.7, 3168.3, 3025.4, 2975.8, 2918.7, 2864.6, 2878.9, 1649.7, 1635.6, 1580.4, 1454.3, 1368.6, 1248.5, 1085.9, 961.4, 732.4, 690.1. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 2H), 7.95 (d, J = 15.9 Hz, 2H), 7.83–7.86 (m, 6H), 7.77 (d, J = 8.7 Hz, 2H), 7.56 to 7.58 (m, 4H), 7.26 (d, J = 15.9 Hz, 2H). EI MS: m/z (rel. abund. %) = M+1 335. Anal. calcd. (%) for C25H18O (334.14): C, 89.79; H, 5.43. Found: C, 89.80; H, 5.42.
1. ,5-Bis(4-methylphenyl)-1,4-pentadien-3-one (8j). Yellow solid, mp 174–176 °C. IR (KBr, cm−1): 3246.4, 3155.7, 3012.7, 2970.2, 2982.4, 2867.8, 2838.7, 1643.8, 1631.5, 1578.1, 1445.6, 1367.2, 1262.5, 1069.9, 960.8, 741.9, 680.9. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 6H), 7.05 (d, J = 15.9 Hz, 2H), 7.25 (m, 4H), 7.42 (m, 4H), 7.73 (d, J = 15.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 187.3, 144.2, 139.1, 135.2, 132.7, 129.1, 129.9, 126.1, 125.9, 22.4. EI MS: m/z (rel. abund. %) = M+1 263. Anal. calcd. (%) for C19H18O (262.14): C, 86.99; H, 6.92. Found: C, 86.94; H, 6.95.
1. ,5-Bis(3-methylphenyl)-1,4-pentadien-3-one (8k). Pale yellow solid; mp 68–70 °C. IR (KBr, cm−1): 3132.6, 3086.8, 3057.6, 2978.9, 2937.4, 2866.2, 2848.7, 1645.6, 1635.7, 1578.1, 1455.3, 1362.7, 1265.2, 1146.7, 1085.4, 961.4, 741.2, 675.6. 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 6H), 7.05 (d, J = 15.9 Hz, 2H), 7.25 (m, 4H), 7.42 (m, 4H), 7.71 (d, J = 15.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 188.3, 143.7, 138.3, 134.4, 131.2, 128.1, 128.2, 125.3, 125.6, 21.9. EI MS: m/z (rel. abund. %) = M+1 263. Anal. calcd. (%) for C19H18O (262.14): C, 86.99; H, 6.92. Found: C, 86.93; H, 6.97.
(1E,3E,6E,8E)-1,9-diphenylnona-1,3,6,8-tetraen-5-one (9a). Yellow powder; mp 144–145 °C. IR (KBr, cm−1): 3021, 3023.1, 2962.6, 2924.4, 2860.5, 2823.3, 1647, 1633, 1604, 1550, 1580, 1447, 1453.2, 1362.2, 1201.2, 1083.3, 966.2, 748.4, 691.2. 1H NMR (400 MHz, CDCl3) δ 6.58 (d, J = 15.2 Hz, 2H), 6.97–7.00 (m, 4H), 7.27–7.52 (m, 12H). EI MS: m/z (rel. abund. %) = M+1 287. Anal. calcd. (%) for C21H18O: C, 88.08; H, 6.34. Found: C, 88.10; H, 6.35.
(1E,3E,6E,8E)-1,9-bis(4-methoxyphenyl)nona-1,3,6,8-tetraen-5-one (9b). Yellow solid; mp 235–237 °C. IR (KBr, cm−1): 3010, 3018.8, 2969.7, 2918.8, 2863.1, 2829.1, 1652, 1632, 1612, 1535, 1580, 1446, 1453.6, 1359.4, 1210.5, 1092.4, 962.3, 748.6, 691.2. 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 6H), 6.56 (d, J = 15.2 Hz, 2H), 6.96–7.00 (m, 4H), 7.25–7.55 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 347. Anal. calcd. (%) for C23H22O3: C, 79.74; H, 6.40. Found: C, 79.75; H, 6.38.
(1E,3E,6E,8E)-1,9-di-p-tolylnona-1,3,6,8-tetraen-5-one (9c). Yellow solid; mp 175–177 °C. IR (KBr, cm−1): 3020, 3028, 2969, 2923, 2862, 2830, 1655, 1628, 1618, 1535, 1575, 1445, 1450.1, 1362.1, 1205.6, 1095.4, 960.1, 740.2, 690.5. 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 6H), 6.56 (d, J = 15.2 Hz, 2H), 6.95–7.00 (m, 4H), 7.25–7.51 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 315. Anal. calcd. (%) for C23H22O: C, 87.86; H, 7.05. Found: C, 87.84; H, 7.07.
(1E,3E,6E,8E)-1,9-bis(4-nitrophenyl)nona-1,3,6,8-tetraen-5-one (9d). Yellow solid; mp 263–266 °C. IR (KBr, cm−1): 3105, 3066, 2975, 2922, 2860, 2830, 1763, 1650, 1632, 1612, 1542, 1511, 1440, 1426.3, 1361.4, 1225.2, 1089.3, 959.2, 715.2, 652.4. 1H NMR (400 MHz, CDCl3) δ 6.57 (d, J = 15.2 Hz, 2H), 6.96–7.05 (m, 4H), 7.23–7.50 (m, 2H), 8.04–8.13 (m, 8H). EI MS: m/z (rel. abund. %) = M+1 377. Anal. calcd. (%) for C21H16N2O5: C, 67.02; H, 4.28; N, 7.44. Found: C, 67.05; H, 4.30; N, 7.45.
(1E,3E,6E,8E)-1,9-bis(4-bromophenyl)nona-1,3,6,8-tetraen-5-one (9e). Pale yellow solid; mp 272–274 °C. IR (KBr, cm−1): 3226, 3122.1, 2962.2, 2910.4, 2862.3, 2817.1, 1635, 1628, 1612, 1540, 1571, 1438, 1430.1, 1337.1, 1248.1, 1090.4, 962.4, 749, 682. 1H NMR (400 MHz, CDCl3) δ 6.57 (d, J = 15.2 Hz, 2H), 6.94–7.02 (m, 4H), 7.24–7.53 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 444, 445. Anal. calcd. (%) for C21H16N2O5: C, 56.79; H, 3.63. Found: C, 56.80; H, 3.65.
(1E,3E,6E,8E)-1,9-bis(4-(dimethylamino)phenyl)nona-1,3,6,8-tetraen-5-one (9f). Yellow solid; mp 262–264 °C. IR (KBr, cm−1): 3108, 3048.2, 2962.2, 2922, 2854, 2808, 1645, 1635, 1612, 1546, 1580, 1445, 1455, 1365, 1202, 1080, 960, 743, 690. 1H NMR (400 MHz, CDCl3) δ 3.22–3.30 (s, 12H), 6.61 (d, J = 15.2 Hz, 2H), 6.96–7.03 (m, 4H), 7.25–7.51 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 373. Anal. calcd. (%) for C25H28N2O (372.22): C, 80.61; H, 7.58; N, 7.52. Found: C, 80.62; H, 7.60; N, 7.55.
(1E,3E,6E,8E)-1,9-bis(4-chlorophenyl)nona-1,3,6,8-tetraen-5-one (9g). Pale yellow solid; mp 222–224 °C. IR (KBr, cm−1): 3010, 2970, 2922, 2861, 2833, 1649, 1635, 1625, 1545, 1530, 1443, 1453, 1361, 1205, 1109.3, 962, 742, 695. 1H NMR (400 MHz, CDCl3) δ 6.53 (d, J = 15.2 Hz, 2H), 6.96–7.01 (m, 4H), 7.26–7.53 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 355, 356. Anal. calcd. (%) for C21H16Cl2O (354.06): C, 71.00; H, 4.54. Found: C, 71.05; H, 4.55.
(1E,3E,6E,8E)-1,9-bis(2-nitrophenyl)nona-1,3,6,8-tetraen-5-one (9h). Yellow solid; mp 265–267 °C. IR (KBr, cm−1): 3107, 3077, 2962, 2938, 2861, 2825, 1649, 1635, 1612, 1540, 1501, 1452, 1423, 1364, 1229, 1189, 961, 743, 691. 1H NMR (400 MHz, CDCl3) δ 6.60 (d, J = 15.2 Hz, 2H), 6.94–7.01 (m, 4H), 7.25–7.55 (m, 6H), 8.06–8.16 (m, 4H). EI MS: m/z (rel. abund. %) = M+1 377. Anal. calcd. (%) for C21H16N2O5: C, 67.02; H, 4.28; N, 7.44. Found: C, 67.03; H, 4.32; N, 7.43.
(1E,3E,6E,8E)-1,9-bis(2-methoxyphenyl)nona-1,3,6,8-tetraen-5-one (9i). Yellow solid; mp 224–226 °C. IR (KBr, cm−1): 3048, 3017, 2907, 2880, 2854.5, 2818, 1642, 1631, 1604, 1575, 1515, 1470, 1453, 1361, 1232, 1132, 945, 735, 695. 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 6H), 6.55 (d, J = 15.2 Hz, 2H), 6.96–7.02 (m, 4H), 7.27–7.52 (m, 10H). EI MS: m/z (rel. abund. %) = M+1 347. Anal. calcd. (%) for C23H22O3 (346.16): C, 79.74; H, 6.40. Found: C, 79.75; H, 6.38.
(1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-one (10a). Yellow solid; mp 137–139 °C. IR (KBr, cm−1): 3348.4, 3267.9, 3148.6, 3024.7, 2970.2, 2952.6, 2865.2, 2830.3, 1643.8, 1634.7, 1607.3, 1542.4, 1575.2, 1443.7, 1450.1, 1362.1, 1246.6, 1185.5, 962.3, 742.1, 691.6. 1H NMR (400 MHz, Acetone-d6) δ 6.62–6.64 (d, J = 15.2 Hz, 2H), 6.85–6.93 (m, 8H), 7.45–7.56 (m, 6H). EI MS: m/z (rel. abund. %) = M+1 261. Anal. calcd. (%) for C19H16O (260.12): C, 87.66; H, 6.19. Found: C, 87.65; H, 6.20.
(1E,4E,6E)-7-(4-methoxyphenyl)-1-phenylhepta-1,4,6-trien-3-one (10b). Yellow solid; mp 167–169 °C. IR (KBr, cm−1): 3117, 3027, 2964, 2939, 2860, 2828, 1650, 1638, 1622, 1548, 1531, 1450, 1429, 1369, 1230, 1190, 960, 742, 690. 1H NMR (400 MHz, Acetone-d6) δ 3.76 (s, 3H), 6.62–6.66 (d, J = 15.2 Hz, 2H), 6.86–6.92 (m, 8H), 7.42–7.7.66 (m, 5H). EI MS: m/z (rel. abund. %) = M+1 291. Anal. calcd. (%) for C20H18O2 (290.13): C, 82.73; H, 6.25. Found: C, 82.71; H, 6.23.
(1E,4E,6E)-1-phenyl-7-p-tolylhepta-1,4,6-trien-3-one (10c). Yellow solid; mp 157–159 °C. IR (KBr, cm−1): 3221.7, 3128.3, 2968.2, 2917.8, 2867.2, 2819.7, 1639.5, 1638.8, 1622.7, 1542.6, 1573.7, 1440.7, 1432.8, 1335.7, 1250.3, 1190.8, 965.3, 745.6, 681.6. 1H NMR (400 MHz, Acetone-d6) δ 2.33 (s, 3H), 6.63–6.66 (d, J = 15.2 Hz, 2H), 6.85–6.92 (m, 8H), 7.42–7.65 (m, 5H). EI MS: m/z (rel. abund. %) = M+1 275. Anal. calcd. (%) for C20H18O (274.14): C, 87.56; H, 6.61. Found: C, 87.63; H, 6.64.
(1E,4E,6E)-7-(4-nitrophenyl)-1-phenylhepta-1,4,6-trien-3-one (10d). Brown solid; mp 177–179 °C. IR (KBr, cm−1): 3242.3, 3152.1, 3013.2, 2976.7, 2981.4, 2860.1, 2839.6, 1642.1, 1634.3, 1572.6, 1447.2, 1368.3, 1264.5, 1070.1, 962.1, 742.2, 681.6. 1H NMR (400 MHz, Acetone-d6) δ 6.63–6.66 (d, J = 15.2 Hz, 2H), 6.92–7.21 (m, 3H), 7.44–7.77 (m, 6H), 8.03–8.17 (m, 4H). EI MS: m/z (rel. abund. %) = M+1 306. Anal. calcd. (%) for C19H15NO3 (305.11): C, 74.74; H, 4.95; N, 4.59. Found: C, 74.72; H, 4.96; N, 4.60.
(1E,4E,6E)-7-(4-bromophenyl)-1-phenylhepta-1,4,6-trien-3-one(10e). Pale yellow solid; mp 211–213 °C. IR (KBr, cm−1): 3245.6, 3165.6, 3025.4, 2975.2, 2932.1, 2863.1, 2839.5, 1657.1, 1652.6, 1575.6, 1462.1, 1360.1, 1271.3, 1077.2, 962.3, 740.1, 690.7. 1H NMR (400 MHz, Acetone-d6) δ 6.60–6.64 (d, J = 15.2 Hz, 2H), 6.97–7.11 (d, 2H), 7.34–7.42 (m, 3H), 7.45–7.75 (m, 8H). EI MS: m/z (rel. abund. %) = M+1 339, 340. Anal. calcd. (%) for C19H15BrO (338.03): C, 67.27; H, 4.46. Found: C, 67.31; H, 4.43.
(1E,4E,6E)-7-(4-(dimethylamino)phenyl)-1-phenylhepta-1,4,6-trien-3-one(10f). Yellow solid; mp 267–269 °C. IR (KBr, cm−1): 3348.1, 3262.2, 3169.8, 3026.3, 2970.2, 2916.8, 2865.1, 2880.9, 1659.6, 1638.7, 1583.6, 1455.4, 1366.1, 1247.2, 1083.1, 962.3, 734.6, 693.2. 1H NMR (400 MHz, Acetone-d6) δ 3.04 (s, 6H), 6.62–6.64 (d, J = 15.2 Hz, 2H), 6.96–7.13 (d, 2H), 7.31–7.43 (m, 3H), 7.45–7.74 (m, 8H). EI MS: m/z (rel. abund. %) = M+1 304. Anal. calcd. (%) for C21H21NO (303.16): C, 83.13; H, 6.98; N, 4.62. Found: C, 83.15; H, 6.96; N, 4.61.
(1E,4E,6E)-7-(4-chlorophenyl)-1-phenylhepta-1,4,6-trien-3-one (10g). Pale yellow solid; mp 177–179 °C. IR (KBr, cm−1): 3156.7, 3068.6, 3025.4, 2970.5, 2927.6, 2862.4, 2832.8, 1658.7, 1636.7, 1612.8, 1545.7, 1571.6, 1446.4, 1426.8, 1365.9, 1270.7, 1039.9, 946.5, 748.5, 689.2. 1H NMR (400 MHz, Acetone-d6) δ 6.60–6.66 (d, J = 15.2 Hz, 2H), 6.97–7.12 (d, 2H), 7.34–7.43 (m, 3H), 7.41–7.74 (m, 8H). EI MS: m/z (rel. abund. %) = M+1 295, 296. Anal. calcd. (%) for C19H15ClO (294.08): C, 77.42; H, 5.13. Found: C, 77.44; H, 5.11.
(1E,4E,6E)-7-(2-nitrophenyl)-1-phenylhepta-1,4,6-trien-3-one (10h). Yellow solid; mp 186–188 °C. IR (KBr, cm−1): 3104.3, 3067.4, 2972.5, 2923.6, 2862.3, 2834.2, 1765.8, 1655.2, 1634.6, 1615.7, 1545.7, 1518.3, 1445.7, 1425.2, 1360.1, 1235.9, 1069.8, 955.7, 725.8, 654.3. 1H NMR (400 MHz, Acetone-d6) δ 6.62–6.63 (d, J = 15.2 Hz, 2H), 6.95–7.25 (m, 3H), 7.41–7.7.71 (m, 6H), 8.07–8.22 (m, 4H). EI MS: m/z (rel. abund. %) = M+1 306. Anal. calcd. (%) for C19H15NO3 (305.11): C, 74.74; H, 4.95; N, 4.59. Found: C, 74.72; H, 4.96; N, 4.60.
(1E,4E,6E)-7-(2-methoxyphenyl)-1-phenylhepta-1,4,6-trien-3-one (10i). Yellow solid; mp 172–174 °C. IR (KBr, cm−1): 3325.7, 3127.5, 3060.7, 2972.5, 2931.2, 2843.6, 2851.6, 1645.8, 1620.8, 1575.1, 1460.6, 1365.3, 1205.5, 1184.8, 964.2, 745.1, 689.6. 1H NMR (400 MHz, Acetone-d6) δ 3.74 (s, 3H), 6.63–6.68 (d, J = 15.2 Hz, 2H), 6.85–6.93 (m, 8H), 7.44–7.63 (m, 5H). EI MS: m/z (rel. abund. %) = M+1291. Anal. calcd. (%) for C19H16O (290.13): C, 82.73; H, 6.25. Found: C, 82.74; H, 6.23.

2.4. Determination of Bovine Lens ARI Activity of Curcuminoids

All the synthesized curcuminoids were tested in vitro for their inhibitory activity against AR isolated from bovine lenses and purified as previously described [33]. The ARI activity of the curcuminoids was assayed spectrophotometrically (UV-1700, Shimadzu, Kyoto, Japan) by monitoring the decrease in the NADPH absorption rate at 340 nm over a period of 4 min at 30 °C, with DL-glyceraldehyde as a substrate. The reaction mixture (900 µL) contained 531 µL of potassium phosphate buffer (0.1 M, pH 6.2), 90 µL of NADPH (1.6 mM in phosphate buffer pH 6.2), 90 µL of bovine lens AR, 90 µL of DL-glyceraldehyde (25 mM in phosphate buffer pH 6.2), 90 µL of deionized water, and 9 µL of curcuminoids at different concentrations in dimethyl sulfoxide (DMSO). The reaction mixture without DL-glyceraldehyde was incubated for 10 min at 30 °C, and then the substrate was added to start the reaction, which was monitored for 4 min. Quercetin, a typical ARI drug, was used as a positive control. The assay was performed in triplicate, and the inhibition percentage was calculated as follows:
A R I   ( % ) =   1 −   ( Δ A   s a m p l e )   − ( Δ A   b l a n k ) ( Δ A   c o n t r o l )   −   ( Δ A   b l a n k )   x   100 ,
where (∆A sample) is the change in the absorbance of the reaction mixture with curcuminoids; (∆A control) is the change in the absorbance of the reaction mixture with DMSO (without curcuminoids); and (∆A blank) is the change in the absorbance of the reaction mixture without the AR enzyme. The results were expressed as 50% inhibitory concentration (IC50) values, calculated from the least-squares regression line of logarithmic concentrations plotted versus the inhibitory activity.

2.5. Molecular Docking Study

Molecular docking studies were performed using AutoDock 4.2.6 and MGLTools 1.5.6 to investigate the intermolecular interactions between the AR enzyme and the most active curcuminoid inhibitor, 10g [34,35]. The three-dimensional crystal structure of bovine AR (the enzyme we used for experiments) is not available in the Protein Data Bank (PDB) database. Hence, the crystal structure of pig AR, complexed with sorbinil (PDB: 1AH0), was used for the docking studies [36]. The structure of 1AH0 is quite similar to bovine lens AR. The MarvinSketch free software tool from the Chemaxon package was used to generate the spatial compound coordinates [37]. The receptor and ligands were prepared with the help of AutoDock tools for molecular docking simulation by adding hydrogen atoms and Kollman charges. A grid box of 60 × 60 × 60 points was defined for the structure to allow the ligands to explore the possible binding site. AutoGrid 4 was used to generate grid maps for AutoDock calculations, where the search space size utilized a grid point of 1.0 Å. The Lamarckian genetic algorithm was used to find the best conformations of the ligand with respect to the target energy grids. Each docking experiment was performed 20 times with 250,000,000 energy evaluations, yielding 20 docked conformations. The docked conformations and the predicted model were visualized using PyMOL version 1.8.0.0 (PyMOL 1.8.0.0) [38]. The binding site for the best conformation of the ligand, with the lowest binding free energy, was analyzed.

3. Results and Discussion

3.1. Chemistry

Three different series of enone analogs of curcumin, such as (i) curcumin analogs that retained the five-carbon spacer between the aryl rings, (ii) curcumin analogs with a seven-carbon spacer, and (iii) curcumin analogs with a nine-carbon spacer, were synthesized to evaluate their ARI activity. Scanned 1H NMR and IR spectral data of synthesized compounds are given in the Supplementary Materials. All the synthesized curcumin analogs contain two identical aryl rings separated by an unsaturated five-carbon spacer with a single carbonyl, whereas some compounds have two different aryl rings (Table 1). These curcuminoids were designed to investigate the effect of the length of the spacer between the two aryl rings. The desired derivatives were obtained in 70%–85% yield after purification. Curcuminoids are known for a poor solubility; however, owing to the extended conjugation between the two aromatic moieties, a good aqueous solubility was observed for the synthesized curcuminoids. Additionally, it was found that the introduction of halogen groups increased the solubility of these curcuminoids in both protic and aprotic solvents such as methanol-water dioxane and DMSO. Therefore, the results obtained in this study would be useful for designing and synthesizing curcuminoids with enhanced aqueous solubility.

3.2. AR Inhibition Study

AR is best characterized as a glucose-reducing NAD(P)H-dependent oxidoreductase enzyme responsible for the pathophysiology of DM disorders [39]. Therefore, the ARI activity of the synthesized curcuminoids was evaluated by measuring the reduction of dl-glyceraldehyde in the presence of NADPH as a reductant. The results showed that all curcuminoids of the novel series displayed a good to moderate activity against AR at micromolar concentrations (Table 2), when compared with that of the known standard quercetin. The compounds tested showed AR inhibition levels from 53.1% ± 0.9% to 75.4% ± 1.9% at the 10 µM concentration. Compounds 8d, 8h, 9c, 9e, and 10g showed promising ARI activities, with IC50 values of 5.73 ± 0.28, 5.95 ± 0.27, 5.11 ± 0.11, 5.78 ± 0.13, and 5.10 ± 0.14 µM, respectively. Furthermore, compounds 8a, 8i, 8j, and 9g showed AR inhibition levels from 56.8% ± 1.2% to 68.7% ± 1.8% at the 10 µM concentration, with IC50 values of 6.04 ± 0.32, 6.12 ± 0.16, 6.08 ± 0.14, and 6.18 ± 0.29 µM, respectively. The dose response plot for compounds 8a, 8b, 9a, 10a, and 10b with standard quercetin is given in the Supplementary Materials (Figure S1). These results suggested that the insertion of the spacer between the two rings allowed a more extensive electronic delocalization, which supports the affinity of the inhibitors to AR. It was also observed that methyl and methoxy derivatives of curcumin (e.g., 8b, 8d, 8h, 8j, 8k, 9b, 9c, 9e, 9i, 10b, 10c, and 10i) exhibited more significant ARI activities than those shown by compounds with other substitutions on the aromatic ring. This indicated that the substitution pattern on the aromatic moiety affected the ARI activity of the derivatives. Additionally, the synthesized curcuminoids might possess the antioxidant activity, as it has been previously reported that methoxy groups are involved in antioxidant properties [40,41]. Previously, curcumin analogs were synthesized and evaluated for inhibitory effects on bovine lens AR activity [40,41]. The result of the structure–activity relationship demonstrated that curcumin analogs possessing the ortho-dihydroxyl group formed a close affinity with AR to exhibit potent inhibitory effects.
It was also observed that halogen-containing curcuminoids (e.g., 8c, 8g, 9e, 9g, 10e, and 10g) exhibited an excellent ARI activity, with IC50 values ranging from 5.10 ± 0.14 to 6.62 ± 0.33 µM. The α, β-double bond is known to decrease ARI activity, while the increase in conjugation promotes the inhibition of AR. It was noted that most of the curcumin analogs with ARI activity retained the phenolic ring substituents. However, a number of the analogs lacking phenolic ring substituents, which were capable of forming stable tertiary carbon-centered radicals, were also active. Similarly, several researchers have tried to enhance the therapeutic properties and stability of curcumin analogs through structural modifications [42,43]. Thus, the observed ARI activity of the curcuminoids is therapeutically important because the low bioavailability of curcumin limits its medicinal application. The results of biological evaluation were further confirmed by the molecular docking studies.

3.3. Molecular Docking

Molecular docking analysis is vital for the design of drugs as it not only highlights the correspondence between the biological activity and binding, but also elucidates the key interactions with the active site. In order to gain some insight about the binding mode of the designed inhibitors, the docking analysis of synthesized curcumin analogues in the active site of pig AR (PDB: 1AH0) were carried out. Herein, to further understand the intermolecular interactions between the most active curcuminoid (10g) and the AR enzyme, molecular docking studies were performed using AutoDock 4.2.6 and MGLTools 1.5.6. Figure 3 shows the interacting mode of curcuminoid 10g in the binding site of AR. As shown in Figure 3, the potent ARI curcuminoid 10g (IC50 = 5.10 µM) fits well into the active site of the AR enzyme.
Curcuminoid 10g demonstrated a prominent steric interaction with AR through the formation of a hydrogen bond between CO and NH of the amino acids Trp20 and Thr19 (Figure 4).
It was observed that the binding pocket could accommodate curcuminoids with various substituents, which allows further modifications to increase the potency.

4. Conclusions

A novel series of curcumin analogs was designed, synthesized, and evaluated in vitro for the inhibition of AR. The biological activity study revealed that all the synthesized curcuminoids exhibited moderate to good ARI activity, which indicated the successful synthesis of AR inhibitors. Importantly, the halogen-containing curcuminoids exhibited excellent ARI activity, thereby providing important evidence for further development of antidiabetic drugs. Molecular docking studies performed on the most active curcumin analog provided a deeper insight into the binding mode of the synthesized curcuminoids, thus creating a basis for further development of potent and selective AR inhibitors to treat diabetes and associated complications.

Supplementary Materials

The following are available online at https://www.mdpi.com/2227-9717/7/7/417/s1. Scanned 1H NMR and IR spectral data of important synthesized compounds and Figure S1. Dose response plot for compounds 8a, 8b, 9a, 10a and 10b with standard quercetin.

Author Contributions

Conceptualization, H.L. and D.K.; Methodology, D.K. and S.D.; Validation, D.K. and H.L.; Formal analysis, D.K. and S.D.; Investigation, D.K. and S.D.; Data curation, D.K.; Writing—original draft preparation, H.L. and D.K.; Writing—review and editing, H.L.; Visualization, H.L. and D.K.; Supervision, H.L.

Funding

This research received no external funding.

Acknowledgments

This research was supported by the KU Research Professor Program of Konkuk University.

Conflicts of Interest

The authors declare no conflict of interest.

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Processes 07 00417 g001 550
Figure 1. Structures of curcumin analogues used in this study.
Figure 1. Structures of curcumin analogues used in this study.
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Processes 07 00417 g002 550
Figure 2. Synthesis of (a) dibenzeledeneacetone, (b) dicinnamalacetone, and (c) trienonanalogs of curcumin.
Figure 2. Synthesis of (a) dibenzeledeneacetone, (b) dicinnamalacetone, and (c) trienonanalogs of curcumin.
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Figure 3. Docking view of curcuminoid 10g (molecular weight = 294.77) (green sticks) in the binding site of AR. The protein structures are shown in ribbon representation.
Figure 3. Docking view of curcuminoid 10g (molecular weight = 294.77) (green sticks) in the binding site of AR. The protein structures are shown in ribbon representation.
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Figure 4. Ligand–receptor interaction mode of curcuminoid 10g with the AR enzyme. The interaction of 10g between oxygen (red) and hydrogen (grey) of amino acids.
Figure 4. Ligand–receptor interaction mode of curcuminoid 10g with the AR enzyme. The interaction of 10g between oxygen (red) and hydrogen (grey) of amino acids.
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Table
Table 1. Synthesis of a series of curcumin analogues.
Table 1. Synthesis of a series of curcumin analogues.
Entry Product Time (hr.) Yield (%) Entry Product Time (hr.) Yield (%)
8a Processes 07 00417 i001 2 85 9e Processes 07 00417 i002 2 84
8b Processes 07 00417 i003 2 84 9f Processes 07 00417 i004 4 70
8c Processes 07 00417 i005 2.5 85 9g Processes 07 00417 i006 2 82
8d Processes 07 00417 i007 2 85 9h Processes 07 00417 i008 3.5 75
8e Processes 07 00417 i009 2 82 9i Processes 07 00417 i010 3 74
8f Processes 07 00417 i011 2.5 80 10a Processes 07 00417 i012 2 85
8g Processes 07 00417 i013 2 84 10b Processes 07 00417 i014 2 84
8h Processes 07 00417 i015 2.5 85 10c Processes 07 00417 i016 3 82
8i Processes 07 00417 i017 2 84 10d Processes 07 00417 i018 2 84
8j Processes 07 00417 i019 2.5 82 10e Processes 07 00417 i020 2 85
8k Processes 07 00417 i021 3 80 10f Processes 07 00417 i022 3.5 80
9a Processes 07 00417 i023 2 80 10g Processes 07 00417 i024 2 84
9b Processes 07 00417 i025 2 78 10h Processes 07 00417 i026 3 81
9c Processes 07 00417 i027 2.5 78 10i Processes 07 00417 i028 3 80
9d Processes 07 00417 i029 3.5 80
Table
Table 2. Inhibitory effects of the curcumin analogues on bovine lens aldose reductase (AR).
Table 2. Inhibitory effects of the curcumin analogues on bovine lens aldose reductase (AR).
Entry Inhibition (%) a IC50 (µM) b Entry Inhibition (%) a IC50 (µM) b
8a 66.3 ± 1.3 6.04 ± 0.32 9e 75.4 ± 1.9 5.78 ± 0.13
8b 64.4 ± 1.2 6.83 ± 0.27 9f 66.7 ± 1.6 6.65 ± 0.31
8c 61.7 ± 1.1 6.23 ± 0.21 9g 68.7 ± 1.8 6.18 ± 0.29
8d 74.4 ± 1.6 5.73 ± 0.28 9h 65.4 ± 1.5 6.72 ± 0.26
8e 64.2 ± 1.2 6.80 ± 0.24 9i 63.6 ± 1.3 7.00 ± 0.30
8f 68.4 ± 1.4 6.23 ± 0.18 10a 67.5 ± 1.7 6.45 ± 0.21
8g 67.5 ± 1.5 6.62 ± 0.33 10b 58.7 ± 1.0 6.54 ± 0.19
8h 63.5 ± 1.3 5.95 ± 0.27 10c 62.4 ± 1.1 6.80 ± 0.16
8i 66.5 ± 1.8 6.12 ± 0.16 10d 54.1 ± 0.9 8.01 ± 0.32
8j 56.8 ± 1.2 6.08 ± 0.14 10e 65.7 ± 1.5 6.57 ± 0.21
8k 64.4 ± 1.4 6.78 ± 0.23 10f 71.4 ± 1.7 5.85 ± 0.16
9a 53.1 ± 0.9 9.02 ± 0.28 10g 68.6 ± 1.6 5.10 ± 0.14
9b 58.8 ± 1.0 10.65 ± 0.34 10h 67.3 ± 1.6 6.62 ± 0.29
9c 67.8 ± 1.7 5.11 ± 0.11 10i 64.6 ± 1.4 6.70 ± 0.15
9d 66.7 ± 1.6 6.64 ± 0.15 Quercetin 81.5 ± 2.2 5.01 ± 0.09
Data are expressed as the means ± standard deviation (n = 3). a The AR inhibitory (ARI) activity was determined at a concentration of 10 μM. b The 50% inhibitory concentration (IC50) values represent the concentration required to decrease the AR activity by 50%, as estimated from the least-squares regression line of logarithmic concentrations (10, 25, 50, and 100µM) vs. % inhibition. Quercetin was used as a positive control.

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Kondhare, D.; Deshmukh, S.; Lade, H. Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking. Processes 2019, 7, 417. https://doi.org/10.3390/pr7070417

AMA Style

Kondhare D, Deshmukh S, Lade H. Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking. Processes. 2019; 7(7):417. https://doi.org/10.3390/pr7070417

Chicago/Turabian Style

Kondhare, Dasharath, Sushma Deshmukh, and Harshad Lade. 2019. "Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking" Processes 7, no. 7: 417. https://doi.org/10.3390/pr7070417

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