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Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P 2 ligands with potent activity against DRV-Resistant HIV-1 variants

Bioorganic & Medicinal Chemistry Letters, ISSN: 0960-894X, Vol: 101, Page: 129651
2024
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Article Description

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P 2-ligands and 4-substituted phenyl sulfonamides as the P 2′ ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC 50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P 2 ligand and a 4- methoxybenzene sulfonamide P 2′ ligand exhibited inhibitory activity IC 50 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-1 DRV R S (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 P 2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

Bibliographic Details

Meng, Sihan; Gao, Yu; Qiang, Guowei; Hu, Zhiwei; Shan, Qi; Wang, Juxian; Wang, Yucheng; Mou, Jie

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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