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A New Class of HIV-1 Integrase Inhibitors:  The 3,3,3‘,3‘-Tetramethyl-1,1‘-spirobi(indan)-5,5‘,6,6‘-tetrol Family

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Department of Chemistry, University of California, San Diego, La Jolla, California 92093-0358, and Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037
Cite this: J. Med. Chem. 2000, 43, 10, 2031–2039
Publication Date (Web):May 2, 2000
https://doi.org/10.1021/jm990600c
Copyright © 2000 American Chemical Society
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    Abstract

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    Integration is a required step in HIV replication, but as yet no inhibitors of the integration step have been developed for clinical use. Many inhibitors have been identified that are active against purified viral-encoded integrase protein; of these, many contain a catechol moiety. Though this substructure contributes potency in inhibitors, it is associated with toxicity and so the utility of catechol-containing inhibitors has been questioned. We have synthesized and tested a systematic series of derivatives of a catechol-containing inhibitor (1) with the goal of identifying catechol isosteres that support inhibition. We find that different patterns of substitution on the aromatic ring suffice for inhibition when Mn2+ is used as a cofactor. Importantly, the efficiency is different when Mg2+, the more likely in vivo cofactor, is used. These data emphasize the importance of assays with Mg2+ and offer new catechol isosteres for use in integrase inhibitors.

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    †

     University of California, San Diego.

    ‡

     The Salk Institute for Biological Studies.

    *

     To whom correspondence should be addressed. J. S. Siegel:  tel, 858-534-5659; fax, 858-822-0386; e-mail, [email protected].

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