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

Arun K. Ghosh, Jacqueline N. Williams, Rachel Y. Ho, Hannah M. Simpson, Shin Ichiro Hattori, Hironori Hayashi, Johnson Agniswamy, Yuan Fang Wang, Irene T. Weber, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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 Ki 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.

Original languageEnglish
Pages (from-to)9722-9737
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number21
DOIs
Publication statusPublished - 2018 Nov 8
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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