Download MendeleyDesign 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, A.K., Williams, J.N., Ho, R.Y., Simpson, H.M., Hattori, S.I., Hayashi, H., Agniswamy, J., Wang, Y.F., Weber, I.T., Mitsuya, H.(2018) J Med Chem 61: 9722-9737
- PubMed: 30354121
- DOI: https://doi.org/10.1021/acs.jmedchem.8b01227
- Primary Citation of Related Structures:
6E7J, 6E9A - PubMed 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 K i of 40 pM and antiviral IC 50 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 ? resolution, respectively, and revealed important interactions in the active site that have not yet been explored.
Organizational Affiliation:
Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States.
