Design and Discovery of Diarylpyridines and Diarylanilines as Novel Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
By using structure-based drug design and isosteric replacement, two sets of derivatives, diarylpyridines (A)1 and diarylanilines (B)2,3, were designed, synthesized and evaluated against wild-type and several drug-resistant HIV-1 viral strains to exploring novel class of next-generation HIV-1 NNRTIs. The results showed that most of the designed compounds exhibited potent anti-HIV-1 activity with EC50 values ranging from low micromolar to nanomolar. However, some compounds displayed expectably high potency with subnanomolar EC50 values against wildtype viral strains, more potent than etravirine (TMC125) in the same assays. Notably, they were also highly effective against infection by multi-RTIresistant strains, thus suggesting highly potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. Our results also revealed important structure-activity relationship (SAR) conclusions for the two sets of compounds (A and B) and strongly support our hypothesis that an NH2 group on the central 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 MM/GBSA (Sybyl 7.2) and CDOCK (DS 2.50) technologies demonstrated the rationality of our hypothesis.
Bingjie Qin Xingtao Tian Xingkai Jiang Zhiyuan Wu Xiaofeng Wang Lan Xie
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
国际会议
武汉
英文
386-387
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）