Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

• 来源期刊: 药学学报（英文版）
• 关键词: HIV-1 NNRTIs NP-DATAs BP-DATAs Positional adaptability Molecular modeling
• 年，卷（期）: 2020,（2）
• 页码范围: 344-357
• 页数: 14页
• 语种: 英文

摘要

In order to improve the positional adaptability of our previously reported naphthyl diaryltria-zines (NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented.These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC5o values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains.Compounds 5j and 6k had the best activity against WT,single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1).Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity.The preliminary structure-activity relationship and PK profiles were also discussed.