Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Molecules. 2020 Mar 30;25(7):1581. doi: 10.3390/molecules25071581.
Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds (EC = 6 nM) and (EC = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC = 0.08 μM). The preliminary structure-activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
支架跳跃是开发非核苷类逆转录酶抑制剂时常用的策略。在此，通过将我们之前发表的 CH(CN)-DABO 中的氰基亚甲基连接子跳跃到依曲韦林 (ETR) 上，设计了 CH(CN)-DAPYs。合成了十八个 CH(CN)-DAPYs，并对其抗 HIV 活性进行了评估。大多数化合物对野生型 (WT) HIV-1 表现出有希望的活性。化合物 (EC = 6 nM) 和 (EC = 8 nM) 对 WT HIV-1 的单位数纳摩尔效力表现出相当的效力。此外，这两种化合物对 K103N 突变体的 EC 值分别为 0.06 和 0.08 μM，与参考药物依非韦伦 (EFV) (EC = 0.08 μM) 相当。初步的构效关系 (SAR) 表明，在 4-氰苯基的 C2 上引入取代基可以提高抗病毒活性。分子对接预测，氰基亚甲基连接子位于由 Y181/Y188 和 V179 残基形成的疏水性腔中。
