Abstract
A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology
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DNA Gyrase / metabolism
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Drug Resistance, Multiple, Bacterial
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Gram-Negative Bacteria / drug effects*
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Gram-Positive Bacteria / drug effects*
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HeLa Cells
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Humans
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Microbial Sensitivity Tests
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Models, Molecular
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemical synthesis
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Topoisomerase II Inhibitors / chemistry
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Topoisomerase II Inhibitors / pharmacology
Substances
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2-methyl-1-(5-(3-((2-methyl-3H-benzoimidazole-5-carbonyl)amino)phenyl)pyridin-2-yl)-1H-benzoimidazole-5-carboxylic acid (2-dimethylaminoethyl)amide
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2-methyl-1-(5-(3-((2-methyl-3H-benzoimidazole-5-carbonyl)amino)phenyl)pyridin-2-yl)-1H-benzoimidazole-5-carboxylic acid (3-dimethylaminopropyl)amide
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Anti-Bacterial Agents
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Benzimidazoles
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N-(4-(dimethylamino)butyl)-2-methyl-1-(5-(3-(2-methyl-1H-benzo(d)imidazole-6-carboxamido)phenyl)pyridin-2-yl)-1H-benzo(d)imidazole-5-carboxamide
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Topoisomerase II Inhibitors
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DNA Gyrase