3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase

Jing Tang; Kasthuraiah Maddali; Mathieu Metifiot; Yuk Y. Sham; Robert Vince; Yves Pommier; Zhengqiang Wang

doi:10.1021/jm1014378

3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase

Jing Tang, Kasthuraiah Maddali, Mathieu Metifiot, Yuk Y. Sham, Robert Vince, Yves Pommier, Zhengqiang Wang

Center for Drug Design

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55 Scopus citations

Abstract

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.

Original language	English (US)
Pages (from-to)	2282-2292
Number of pages	11
Journal	Journal of medicinal chemistry
Volume	54
Issue number	7
DOIs	https://doi.org/10.1021/jm1014378
State	Published - Apr 14 2011

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title = "3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase",

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AU - Sham, Yuk Y.

AU - Vince, Robert

AU - Pommier, Yves

AU - Wang, Zhengqiang

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AB - Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.

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3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase

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