Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China.
PLoS One. 2020 Jul 22;15(7):e0235483. doi: 10.1371/journal.pone.0235483. eCollection 2020.
A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.
本工作设计、合成并评价了一系列强效的 HIV-1 蛋白酶抑制剂，它们含有作为 P2-配体的各种哌啶类似物、作为 P2'-配体的 4-取代苯磺酰胺和作为 P1'-配体的疏水性环丙基。在这 24 个目标化合物中，许多化合物对 HIV-1 蛋白酶表现出优异的活性，半数最大抑制浓度（IC50）值低于 20 nM。特别是含有（R）-哌啶-3-甲酰胺作为 P2-配体和 4-甲氧基苯磺酰胺作为 P2'-配体的化合物 22a 表现出最有效的抑制活性，IC50 值为 3.61 nM。更重要的是，22a 对野生型和达芦那韦（DRV）耐药的 HIV-1 变异体的抑制活性分别为 42%和 26%。此外，22a 与 HIV-1 蛋白酶的分子对接提供了对配体结合特性的深入了解，这对于进一步的研究具有重要价值。
