Abstract
Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Quinolones / chemical synthesis
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4-Quinolones / chemistry
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4-Quinolones / pharmacology*
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology*
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Cell Proliferation / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hepacivirus / drug effects*
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Hepacivirus / genetics
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Humans
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Microbial Sensitivity Tests
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Molecular Structure
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Real-Time Polymerase Chain Reaction
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Replicon / drug effects*
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Replicon / genetics
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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4-Quinolones
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4-quinolone-3-carboxylic acid
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Antiviral Agents
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Carboxylic Acids
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Enzyme Inhibitors
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus