Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies

• Published in: Journal of medicinal chemistry Vol. 61; no. 21; pp. 9722 - 9737
• Main Authors: Ghosh, Arun K, Williams, Jacqueline N, Ho, Rachel Y, Simpson, Hannah M, Hattori, Shin-ichiro, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T, Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2018; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Antimicrobial agents; BASIC BIOLOGICAL SCIENCES; Catalytic Domain; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Drug Design; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Inhibitors; Life Sciences & Biomedicine; Ligands; Models, Molecular; Oxazolidinones - chemical synthesis; Oxazolidinones - chemistry; Oxazolidinones - metabolism; Oxazolidinones - pharmacology; Peptides and proteins; Pharmacology & Pharmacy; Reaction products; Science & Technology; Stereoisomerism; Structure-Activity Relationship; DIMERIZATION INHIBITION; DARUNAVIR; RESOLUTION CRYSTAL-STRUCTURES; REPLICATION; MECHANISM; VARIANTS; DRUG-RESISTANT MUTANTS; TMC114; ANTIRETROVIRAL THERAPY; BACKBONE
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01227

We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme K i of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.