2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2024 Feb 9:101:129651. doi: 10.1016/j.bmcl.2024.129651.
Sihan Meng 1,  Yu Gao 2,  Guowei Qiang 3,  Zhiwei Hu 4,  Qi Shan 2,  Juxian Wang 5,  Yucheng Wang 6,  Jie Mou 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221006, China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
  • 3 Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221006, China.
  • 4 School of Basic Medicine, Xuzhou Medical University, Xuzhou 221006, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: imbjxwang@163.com.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: wangyucheng@imb.pumc.edu.cn.
  • 7 Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221006, China. Electronic address: mou.jie@126.com.
PMID: 38342391 DOI: 10.1016/j.bmcl.2024.129651
Abstract

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.

Keywords

Antiviral activity; Darunavir-resistant HIV-1 protease variant; Enzymatic inhibitory activity; HIV-1 protease inhibitors; Phenylacetamide derivatives.

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