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
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. Sev...
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| Published in | Journal of medicinal chemistry Vol. 61; no. 21; pp. 9722 - 9737 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
08.11.2018
Amer Chemical Soc American Chemical Society (ACS) |
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| Online Access | Get full text |
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| 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 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. |
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| AbstractList | 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. 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. 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 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. 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. 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 IC50 of 31 nM. Inhibitors 4k and 41 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 angstrom resolution, respectively, and revealed important interactions in the active site that have not yet been explored. 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.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. |
| Author | Agniswamy, Johnson Williams, Jacqueline N Ghosh, Arun K Simpson, Hannah M Hayashi, Hironori Mitsuya, Hiroaki Ho, Rachel Y Hattori, Shin-ichiro Weber, Irene T Wang, Yuan-Fang |
| AuthorAffiliation | Department of Biology, Molecular Basis of Disease National Center for Global Health and Medicine Research Institute Departments of Infectious Diseases and Hematology Experimental Retrovirology Section, HIV and AIDS Malignancy Branch Department of Chemistry and Department of Medicinal Chemistry Department of Refractory Viral Infections National Cancer Institute, National Institutes of Health |
| AuthorAffiliation_xml | – name: Department of Refractory Viral Infections – name: Department of Biology, Molecular Basis of Disease – name: Department of Chemistry and Department of Medicinal Chemistry – name: Departments of Infectious Diseases and Hematology – name: National Cancer Institute, National Institutes of Health – name: National Center for Global Health and Medicine Research Institute – name: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch – name: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States – name: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States – name: Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, United States – name: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto 860-8556, Japan – name: Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan |
| Author_xml | – sequence: 1 givenname: Arun K orcidid: 0000-0003-2472-1841 surname: Ghosh fullname: Ghosh, Arun K email: akghosh@purdue.edu organization: Department of Chemistry and Department of Medicinal Chemistry – sequence: 2 givenname: Jacqueline N surname: Williams fullname: Williams, Jacqueline N organization: Department of Chemistry and Department of Medicinal Chemistry – sequence: 3 givenname: Rachel Y surname: Ho fullname: Ho, Rachel Y organization: Department of Chemistry and Department of Medicinal Chemistry – sequence: 4 givenname: Hannah M surname: Simpson fullname: Simpson, Hannah M organization: Department of Chemistry and Department of Medicinal Chemistry – sequence: 5 givenname: Shin-ichiro surname: Hattori fullname: Hattori, Shin-ichiro organization: National Center for Global Health and Medicine Research Institute – sequence: 6 givenname: Hironori surname: Hayashi fullname: Hayashi, Hironori organization: National Center for Global Health and Medicine Research Institute – sequence: 7 givenname: Johnson surname: Agniswamy fullname: Agniswamy, Johnson organization: Department of Biology, Molecular Basis of Disease – sequence: 8 givenname: Yuan-Fang surname: Wang fullname: Wang, Yuan-Fang organization: Department of Biology, Molecular Basis of Disease – sequence: 9 givenname: Irene T orcidid: 0000-0003-4876-7393 surname: Weber fullname: Weber, Irene T organization: Department of Biology, Molecular Basis of Disease – sequence: 10 givenname: Hiroaki surname: Mitsuya fullname: Mitsuya, Hiroaki organization: National Cancer Institute, National Institutes of Health |
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| Keywords | DIMERIZATION INHIBITION DARUNAVIR RESOLUTION CRYSTAL-STRUCTURES REPLICATION MECHANISM VARIANTS DRUG-RESISTANT MUTANTS TMC114 ANTIRETROVIRAL THERAPY BACKBONE |
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| Snippet | 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... 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... |
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| StartPage | 9722 |
| SubjectTerms | Antimicrobial agents BASIC BIOLOGICAL SCIENCES Catalytic Domain Chemistry Techniques, Synthetic Chemistry, Medicinal Drug Design HIV Protease - chemistry HIV Protease - metabolism HIV Protease Inhibitors - chemical synthesis HIV Protease Inhibitors - chemistry HIV Protease Inhibitors - metabolism HIV Protease Inhibitors - pharmacology HIV-1 - drug effects HIV-1 - enzymology Inhibitors Life Sciences & Biomedicine Ligands Models, Molecular Oxazolidinones - chemical synthesis Oxazolidinones - chemistry Oxazolidinones - metabolism Oxazolidinones - pharmacology Peptides and proteins Pharmacology & Pharmacy Reaction products Science & Technology Stereoisomerism Structure-Activity Relationship |
| 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 |
| URI | http://dx.doi.org/10.1021/acs.jmedchem.8b01227 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000449889200020 https://www.ncbi.nlm.nih.gov/pubmed/30354121 https://www.proquest.com/docview/2125314460 https://www.osti.gov/servlets/purl/1484805 https://pubmed.ncbi.nlm.nih.gov/PMC6541917 |
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