Abstract
Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / pharmacology*
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Binding Sites
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Cell Line
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Cell Survival / drug effects
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Cell Transformation, Viral / drug effects
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Computer Simulation
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Crystallography, X-Ray
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HIV / drug effects
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HIV Reverse Transcriptase / antagonists & inhibitors*
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Humans
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Microbial Sensitivity Tests
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Pyridones / chemical synthesis
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Pyridones / chemistry
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Pyridones / pharmacology*
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry*
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Reverse Transcriptase Inhibitors / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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Pyridones
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase