Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

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• 作者：Bingjie Qin ; Xingkai Jiang ; Hong Lu ; Xingtao Tian ; Florent Barbault ; Li Huang ; Keduo Qian ; Chin-Ho Chen ; Rong Huang ; Shibo Jiang ; Kuo-Hsiung Lee ; Lan Xie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 8, 2010
• 年：2010
• 卷：53
• 期：13
• 页码：4906-4916
• 全文大小：932K
• 年卷期：v.53,no.13(July 8, 2010)
• ISSN：1520-4804

文摘

By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2-diamine derivatives were synthesized and evaluated against wild type HIV-1 and drug-resistant viral strains, resulting in the discovery of diarylaniline derivatives as a distinct class of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents. The most promising compound 37 showed significant EC₅₀ values of 0.003−0.032 μM against HIV-1 wild-type strains and of 0.005−0.604 μM against several drug-resistant strains. Current results also revealed important structure−activity relationship (SAR) conclusions for diarylanilines and strongly support our hypothesis that an NH₂ group on the central benzene ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with molecular mechanism/general Born surface area (MM/GBSA) technology demonstrated the rationality of our hypothesis.