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Publication Abstract from PubMed

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 A resolution, respectively, and revealed important interactions in the active site that have not yet been explored.

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.,Ghosh AK, Williams JN, Ho RY, Simpson HM, Hattori SI, Hayashi H, Agniswamy J, Wang YF, Weber IT, Mitsuya H J Med Chem. 2018 Oct 24. doi: 10.1021/acs.jmedchem.8b01227. PMID:30354121^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.