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  3. Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands

Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands

  • Eur J Med Chem. 2025 Jun 20:297:117880. doi: 10.1016/j.ejmech.2025.117880.
Arun K Ghosh 1,  Ryan Shaktah 2,  Ajay K Ghosh 2,  Megan E Johnson 2,  Dipendra Bhandari 3,  Masayuki Amano 4,  Manabu Aoki 5,  Andrey Kovalevsky 3,  Hiroaki Mitsuya 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: akghosh@purdue.edu.
  • 2 Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
  • 3 Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA.
  • 4 Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan.
  • 5 Department of Medical Technology, Kumamoto University School of Medicine, Kumamoto, 861-5598, Japan.
  • 6 Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556, Japan; Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
PMID: 40644923 DOI: 10.1016/j.ejmech.2025.117880
Abstract

We report here the design, synthesis and evaluation of a series of HIV-1 Protease Inhibitors that incorporate substituted oxaspirocyclic carbamate derivatives to serve as the P2 ligands. Various substituted ligand derivatives were synthesized in a racemic manner, using a tandem Prins/pinacol reaction as the key reaction. This reaction sets the relative stereochemistry of the oxaspirocyclic template in a highly diastereoselective manner. Reaction of the resulting ketone with enantiopure (S)-tert-butyl sulfinamide provided a convenient pathway to resolve the oxaspirocyclic ketone derivatives. The absolute stereochemical identity was determined by X-ray crystallography. The structure-activity studies demonstrate the effect of the stereochemistry of the oxaspirocyclic ring systems as well as the substitution effect on the aromatic ring. Several inhibitors exhibited potent HIV-1 protease inhibitory activity. One of these inhibitors displayed subnanomolar HIV-1 protease affinity and also exhibited potent Antiviral activity. A high-resolution X-ray crystal structure of this inhibitor-bound HIV-1 protease show that the oxaspirocyclic P2 ligand forms an unconventional C-H⋯O bond with the backbone carboxyl group of Gly48' and an interesting N-H … π interaction with the aromatic ring in the S2 subsite of HIV-1 protease active site.

Keywords

Antiviral; Backbone binding; Darunavir; HIV-1 protease; Inhibitors; Oxaspirocyclic; X-ray crystal structure.

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