Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.

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.

• Authors: Bing Li, Ramdas Pai, Ming Di, Daniel Aiello, Marjorie H Barnes, Michelle M Butler, Tommy F Tashjian, Norton P Peet, Terry L Bowlin, Donald T Moir
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 24 Pg. 10896-908 (Dec 27 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23231076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(7-((4'-chlorobiphenyl-4-yl)methoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid
• 3-(7-(biphenyl-4-ylmethoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid
• Anti-Bacterial Agents
• Coumarins
• DNA, Bacterial
• DNA, Single-Stranded
• Ciprofloxacin
• DnaB Helicases

Topics

• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Bacillus anthracis (drug effects, enzymology)
• Ciprofloxacin (pharmacology)
• Coumarins (chemical synthesis, chemistry, pharmacology)
• DNA, Bacterial (genetics, metabolism)
• DNA, Single-Stranded (genetics, metabolism)
• DnaB Helicases (antagonists & inhibitors, chemistry, metabolism)
• Drug Resistance, Bacterial
• Enzyme Assays
• Fluorescence Resonance Energy Transfer
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Microbial Sensitivity Tests
• Staphylococcus aureus (drug effects, enzymology)
• Structure-Activity Relationship