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Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Nov 01; Vol. 27 (21), pp. 4925-4931. Date of Electronic Publication: 2017 Sep 06. - Publication Year :
- 2017
-
Abstract
- Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K <subscript>i</subscript> =13.2nM, IC <subscript>50</subscript> =22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (K <subscript>i</subscript> =62pM and 14pM, respectively) and antiviral activity (IC <subscript>50</subscript> =5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites
Crystallography, X-Ray
HIV Protease chemistry
HIV Protease genetics
HIV Protease Inhibitors chemistry
HIV Protease Inhibitors metabolism
HIV-1 enzymology
Inhibitory Concentration 50
Ligands
Macrocyclic Compounds chemical synthesis
Macrocyclic Compounds metabolism
Molecular Dynamics Simulation
Mutation
Protein Structure, Tertiary
Pyrrolidinones chemistry
Structure-Activity Relationship
Drug Design
HIV Protease metabolism
HIV Protease Inhibitors chemical synthesis
Macrocyclic Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 27
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 28958624
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.09.003