Abstract
The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9-18-fold increased potency against Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC(50) values of 3 and 1 μM, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC(50)/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains, with MIC values ranging between 0.5 and 4.2 μg/mL.
Publication types
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Research Support, N.I.H., Extramural
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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Bacillus anthracis / drug effects
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Bacillus anthracis / enzymology*
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Ciprofloxacin / pharmacology
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Coumarins / chemical synthesis*
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Coumarins / chemistry
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Coumarins / pharmacology
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DNA, Bacterial / genetics
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DNA, Bacterial / metabolism
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DNA, Single-Stranded / genetics
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DNA, Single-Stranded / metabolism
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DnaB Helicases / antagonists & inhibitors*
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DnaB Helicases / chemistry
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DnaB Helicases / metabolism
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Drug Resistance, Bacterial
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Enzyme Assays
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Fluorescence Resonance Energy Transfer
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Microbial Sensitivity Tests
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology*
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Structure-Activity Relationship
Substances
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3-(7-((4'-chlorobiphenyl-4-yl)methoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid
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3-(7-(biphenyl-4-ylmethoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid
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Anti-Bacterial Agents
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Coumarins
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DNA, Bacterial
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DNA, Single-Stranded
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Ciprofloxacin
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DnaB Helicases