Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants
Copyright © 2024 Elsevier Ltd. All rights reserved..
A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:101 |
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| Enthalten in: |
Bioorganic & medicinal chemistry letters - 101(2024) vom: 15. März, Seite 129651 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Sihan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmcl.2024.129651 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants |
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| 520 | |a A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antiviral activity | |
| 650 | 4 | |a Darunavir-resistant HIV-1 protease variant | |
| 650 | 4 | |a Enzymatic inhibitory activity | |
| 650 | 4 | |a HIV-1 protease inhibitors | |
| 650 | 4 | |a Phenylacetamide derivatives | |
| 650 | 7 | |a Darunavir |2 NLM | |
| 650 | 7 | |a YO603Y8113 |2 NLM | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a p16 protease, Human immunodeficiency virus 1 |2 NLM | |
| 650 | 7 | |a EC 3.4.23.- |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a HIV Protease |2 NLM | |
| 650 | 7 | |a EC 3.4.23.- |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a Benzeneacetamides |2 NLM | |
| 700 | 1 | |a Gao, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Qiang, Guowei |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Zhiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Juxian |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yucheng |e verfasserin |4 aut | |
| 700 | 1 | |a Mou, Jie |e verfasserin |4 aut | |
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