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  3. Design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing pyrrolidine-derived P2 ligands to combat drug-resistant variant

Design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing pyrrolidine-derived P2 ligands to combat drug-resistant variant

  • Eur J Med Chem. 2023 Jul 5;255:115389. doi: 10.1016/j.ejmech.2023.115389.
Huiyu Zhou 1,  Ling Ma 1,  Biao Dong 1,  Juxian Wang 1,  Guoning Zhang 1,  Minghua Wang 1,  Shan Cen 1,  Mei Zhu 2,  Qi Shan 3,  Yucheng Wang 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 3 Tianjin Institute of Pharmaceutical Research, Tianjin, 300462, China. Electronic address: [email protected].
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 37120996 DOI: 10.1016/j.ejmech.2023.115389
Abstract

The design, synthesis, and biological evaluation of a novel series of HIV-1 Protease Inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2' ligands were described. A number of inhibitors demonstrated potent efficacy in both Enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2' ligand displayed exceptional Enzyme inhibitory activity with an IC50 value of 0.32 nM. Furthermore, 34b also exhibited robust Antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC50 values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 Protease Inhibitors.

Keywords

Antiviral activity; Drug-resistant variant; Enzyme inhibitory activity; HIV-1 protease inhibitors; Molecular modelling; Pyrrolidine.

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