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.
Bioorg Med Chem. 2022 Jan 1;53:116531. doi: 10.1016/j.bmc.2021.116531. Epub 2021 Dec 3.
To explore the chemical space around the entrance channel of the HIV-1 reverse transcriptase (RT) binding pocket, we innovatively designed and synthesized a series of novel indolylarylsulfones (IASs) bearing phenylboronic acid and phenylboronate ester functionalities at the indole-2-carboxamide as new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) through structure-based drug design. All the newly synthesized compounds exhibited excellent to moderate potency against wild-type (WT) HIV-1 with EC values ranging from 6.7 to 42.6 nM. Among all, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide and (4-ethylphenyl) boronate ester substituted indole-2-carboxamide were found to be the most potent inhibitors (EC = 8.5 nM, SI = 3310; EC = 6.7 nM, SI = 3549, respectively). Notably, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide maintained excellent activities against the single HIV-1 mutants L100I (EC = 7.3 nM), K103N (EC = 9.2 nM), as well as the double mutant V106A/F227L (EC = 21.1 nM). Preliminary SARs and molecular modelling studies are also discussed in detail.
为了探索 HIV-1 逆转录酶 (RT) 结合口袋入口通道周围的化学空间，我们通过基于结构的药物设计，创新性地设计并合成了一系列新型吲哚芳基砜 (IAS)，其吲哚-2-甲酰胺上带有苯硼酸和苯硼酸酯官能团，作为新型 HIV-1 非核苷逆转录酶抑制剂 (NNRTIs)。所有新合成的化合物对野生型 (WT) HIV-1 均表现出优异至中等的抑制活性，EC 值范围为 6.7 至 42.6 nM。在所有化合物中，(3-乙基苯基)硼酸取代的吲哚-2-甲酰胺和(4-乙基苯基)硼酸酯取代的吲哚-2-甲酰胺表现出最强的抑制活性（EC = 8.5 nM，SI = 3310；EC = 6.7 nM，SI = 3549）。值得注意的是，(3-乙基苯基)硼酸取代的吲哚-2-甲酰胺对单突变体 L100I（EC = 7.3 nM）、K103N（EC = 9.2 nM）以及双突变体 V106A/F227L（EC = 21.1 nM）仍保持着优异的活性。详细讨论了初步的 SAR 和分子建模研究。
