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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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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 |
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author | Zhou, Huiyu Zhu, Mei Ma, Ling Zhou, Jinming Dong, Biao Zhang, Guoning Cen, Shan Wang, Yucheng Wang, Juxian |
author_facet | Zhou, Huiyu Zhu, Mei Ma, Ling Zhou, Jinming Dong, Biao Zhang, Guoning Cen, Shan Wang, Yucheng Wang, Juxian |
author_sort | Zhou, Huiyu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7375528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-73755282020-08-04 Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study Zhou, Huiyu Zhu, Mei Ma, Ling Zhou, Jinming Dong, Biao Zhang, Guoning Cen, Shan Wang, Yucheng Wang, Juxian PLoS One Research Article 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. Public Library of Science 2020-07-22 /pmc/articles/PMC7375528/ /pubmed/32697773 http://dx.doi.org/10.1371/journal.pone.0235483 Text en © 2020 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Zhou, Huiyu Zhu, Mei Ma, Ling Zhou, Jinming Dong, Biao Zhang, Guoning Cen, Shan Wang, Yucheng Wang, Juxian Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title | Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title_full | Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title_fullStr | Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title_full_unstemmed | Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title_short | Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study |
title_sort | piperidine scaffold as the novel p2-ligands in cyclopropyl-containing hiv-1 protease inhibitors: structure-based design, synthesis, biological evaluation and docking study |
topic | Research Article |
url | 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 |
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