Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2diamine 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//M 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.
Bingjie Qin Shibo Jiang Kuo-Hsiung Lee Lan Xie Xingkai Jiang Hong Lu Xingtao Tian Florent Barbault Li Huang Keduo Qian Chin-Ho Chen Rong Huang
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China Lindsley F.Kimball Research Institute, New York Blood Center, New York, New York 10065 Natural Products Research Laboratories, University of North Carolina, Chapel Hill, North Carolina 27 ITODYS, Universite Paris Diderot-CNRSVMR 7086,15 rue Jean de Baif, 75205 Paris, France Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, North Carolin
国际会议
武汉
英文
388-398
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）