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 (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
Keywords:
Drug resistance; HIV protease; Macrocyclic inhibitors; P1′-P2′ ligands; Structure-based design.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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Drug Design*
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HIV Protease / chemistry
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HIV Protease / genetics
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HIV Protease / metabolism*
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HIV Protease Inhibitors / chemical synthesis*
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HIV Protease Inhibitors / chemistry
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HIV Protease Inhibitors / metabolism
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HIV-1 / enzymology
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Inhibitory Concentration 50
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Ligands
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry*
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Macrocyclic Compounds / metabolism
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Molecular Dynamics Simulation
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Mutation
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Protein Structure, Tertiary
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Pyrrolidinones / chemistry
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Structure-Activity Relationship
Substances
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HIV Protease Inhibitors
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Ligands
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Macrocyclic Compounds
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Pyrrolidinones
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HIV Protease
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p16 protease, Human immunodeficiency virus 1