6,7-Dihydroxyisoindolin-1-one and 7,8-Dihydroxy-3,4-Dihydroisoquinolin- 1(2H)-one Based HIV-1 Integrase Inhibitors

Author(s): Xue Zhi Zhao, Mathieu Métifiot, Steven J. Smith, Kasthuraiah Maddali, Christophe Marchand, Stephen H. Hughes, Yves Pommier, Terrence R. Burke, Jr.

Journal Name: Current Topics in Medicinal Chemistry

Volume 16 , Issue 4 , 2016

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Graphical Abstract:


Integrase (IN) is an essential viral enzyme required for HIV-1 replication, which has been targeted by anti-AIDS therapeutics. Integrase strand transfer inhibitors (INSTIs) represent a new class of antiretroviral agents developed for the treatment of HIV-1 infections. Important structural features that are shared by many INSTIs include a coplanar arrangement of three heteroatoms that chelate two catalytic Mg2+ ions in the IN active site and a linked halophenyl ring that binds in the hydrophobic pocket formed by the complex of IN with viral DNA. We recently reported bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors. In the current study, we modified these inhibitors in three ways. First, we increased the spacer length between the metalchelating triad and the halophenyl group. Second, we replaced the indoline [5,6] bicycle with a fused dihydroxyisoquinolinones [6,6] ring system. Finally, we prepared bis-6,7-dihydroxyisoindolin-1-one-4-sulfonamides as dimeric HIV-1 IN inhibitors. These new analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays.

Keywords: HIV-1 integrase, Inhibitor, Metal-chelating, Sulfonamide.

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Article Details

Year: 2016
Published on: 14 October, 2015
Page: [435 - 440]
Pages: 6
DOI: 10.2174/1568026615666150813150058
Price: $65

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