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Design, Synthesis and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles.

Design, Synthesis and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles.
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Kang D, Fang Z, Li Z, Huang B, Zhang H, Lu X, Xu H, Zhou Z, Ding X, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X,


Kang D, Fang Z, Li Z, Huang B, Zhang H, Lu X, Xu H, Zhou Z, Ding X, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X, (click to view)

Kang D, Fang Z, Li Z, Huang B, Zhang H, Lu X, Xu H, Zhou Z, Ding X, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X,

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Journal of medicinal chemistry 2016 8 19()

Abstract

We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single digit) nanomolar EC50 values towards a panel of wild-type (WT), single-mutant and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5- to 7-fold greater against Y181C, Y188L, E138K and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 >227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159,101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.

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