Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
Eur J Med Chem. 2023 Nov 5;259:115686. doi: 10.1016/j.ejmech.2023.115686. Epub 2023 Jul 29.
To develop more potent HIV-1 inhibitors against a variety of NNRTIs-resistant strains, a series of 5-cyano substituted diarylpyridines was designed based on the cocrystal structural analysis. Among them, I-5b showed the greatest potency (EC = 5.62-171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC values of 9.37 nM, being much superior to that of NVP (EC = 5128 nM) and EFV (EC = 114 nM) and comparable to that of ETR (EC = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT enzyme inhibitory activity (IC = 0.094-12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking.
为了开发针对多种 NNRTIs 耐药株的更有效的 HIV-1 抑制剂，基于共晶结构分析，设计了一系列 5-氰基取代的二芳基吡啶。其中，I-5b 对野生型（WT）和突变 HIV-1 株显示出最大的效力（EC=5.62-171 nM）。特别是对于 K103N，I-5b 表现出出色的活性，EC 值为 9.37 nM，远优于 NVP（EC=5128 nM）和 EFV（EC=114 nM），与 ETR（EC=3.45 nM）相当。此外，所有化合物的靶点均为 HIV-1 RT，具有中等的 RT 酶抑制活性（IC=0.094-12.0 μM）。此外，通过分子对接详细阐述了代表性化合物与 RT 的结合模式。
