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Title: 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

Abstract

In this work, 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.

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [2];  [2];  [3];  [3]; ORCiD logo [3];  [4]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
  3. Georgia State Univ., Atlanta, GA (United States)
  4. National Center for Global Health and Medicine Research Inst., Tokyo (Japan); Kumamoto Univ. (Japan). Graduate School of Biomedical Sciences; National Inst. of Health (NIH), Bethesda, MD (United States). National Cancer Inst.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Cancer Institute (NCI); Ministry of Education, Culture, Sports, Science and Technology (MEXT); Ministry of Health, Welfare, and Labor of Japan
OSTI Identifier:
1484805
Grant/Contract Number:  
GM53386; GM62920; W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 21; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Antimicrobial agents; Peptides and proteins; Reaction products; Ligands; Inhibitors

Citation Formats

Ghosh, Arun K., Williams, Jacqueline N., Ho, Rachel Y., Simpson, Hannah M., Hattori, Shin-ichiro, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., and Mitsuya, Hiroaki. 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. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b01227.
Ghosh, Arun K., Williams, Jacqueline N., Ho, Rachel Y., Simpson, Hannah M., Hattori, Shin-ichiro, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., & Mitsuya, Hiroaki. 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. United States. doi:10.1021/acs.jmedchem.8b01227.
Ghosh, Arun K., Williams, Jacqueline N., Ho, Rachel Y., Simpson, Hannah M., Hattori, Shin-ichiro, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., and Mitsuya, Hiroaki. Wed . "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". United States. doi:10.1021/acs.jmedchem.8b01227. https://www.osti.gov/servlets/purl/1484805.
@article{osti_1484805,
title = {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},
author = {Ghosh, Arun K. and Williams, Jacqueline N. and Ho, Rachel Y. and Simpson, Hannah M. and Hattori, Shin-ichiro and Hayashi, Hironori and Agniswamy, Johnson and Wang, Yuan-Fang and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {In this work, 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.},
doi = {10.1021/acs.jmedchem.8b01227},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 21,
volume = 61,
place = {United States},
year = {2018},
month = {10}
}

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Cited by: 3 works
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