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
| Autor: | Arun K. Ghosh, Jacqueline N. Williams, Rachel Y. Ho, Hannah M. Simpson, Shin-ichiro Hattori, Hironori Hayashi, Johnson Agniswamy, Yuan-Fang Wang, Irene T. Weber, Hiroaki Mitsuya |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine 010405 organic chemistry 030106 microbiology Stereoisomerism Chemistry Techniques Synthetic HIV Protease Inhibitors Ligands 01 natural sciences Article 0104 chemical sciences Structure-Activity Relationship 03 medical and health sciences HIV Protease Catalytic Domain Drug Design Drug Discovery HIV-1 Molecular Medicine Oxazolidinones |
| Zdroj: | Journal of Medicinal Chemistry. 61:9722-9737 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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