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Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study

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 co...

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Detalles Bibliográficos
Autores principales: Zhou, Huiyu, Zhu, Mei, Ma, Ling, Zhou, Jinming, Dong, Biao, Zhang, Guoning, Cen, Shan, Wang, Yucheng, Wang, Juxian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375528/
https://www.ncbi.nlm.nih.gov/pubmed/32697773
http://dx.doi.org/10.1371/journal.pone.0235483
Descripción
Sumario: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 (IC(50)) 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 IC(50) 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.