Open AccessDesign 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
Author(s) -
Arun K. Ghosh,
Jacqueline N. Williams,
Rachel Y. Ho,
Hannah M. Simpson,
Shin-ichiro Hattori,
Hironori Hayashi,
Johnson Agniswamy,
YuanFang Wang,
Irene T. Weber,
Hiroaki Mitsuya
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01227
Subject(s) - chemistry , darunavir , bicyclic molecule , protease , stereochemistry , ligand (biochemistry) , hiv 1 protease , enzyme , enzyme inhibitor , chemical synthesis , structure–activity relationship , combinatorial chemistry , human immunodeficiency virus (hiv) , in vitro , biochemistry , virology , antiretroviral therapy , viral load , receptor , biology
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 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.