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.

J Med Chem 2018 11 24;61(21):9722-9737. Epub 2018 Oct 24.

Department of Refractory Viral Infections , National Center for Global Health and Medicine Research Institute , Tokyo 162-8655 , Japan.

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 of 40 pM and antiviral IC 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.

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Source
http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01227
Publisher Site
http://dx.doi.org/10.1021/acs.jmedchem.8b01227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541917PMC
November 2018
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