Abstract
Benzimidazole 5-carboxamide derivatives from a combinatorial screening library were discovered as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive "drug-like" lead structure for further optimization and the development of potential HCV therapeutics.
MeSH terms
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacology
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology
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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 / enzymology*
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / metabolism
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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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Antiviral Agents
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Benzimidazoles
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Enzyme Inhibitors
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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RNA-Dependent RNA Polymerase