Abstract
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.
Keywords:
Antibacterial; Fluoroquinoline; Gyrase; MRSA; NBTI; Topoisomerase.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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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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DNA Gyrase / metabolism*
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DNA Topoisomerase IV / antagonists & inhibitors*
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DNA Topoisomerase IV / metabolism
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Dose-Response Relationship, Drug
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Ether-A-Go-Go Potassium Channels / metabolism
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Guinea Pigs
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Humans
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Microbial Sensitivity Tests
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Molecular Structure
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology
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Streptococcus pyogenes / drug effects
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Streptococcus pyogenes / enzymology
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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*
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Topoisomerase Inhibitors / chemical synthesis
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Topoisomerase Inhibitors / chemistry
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Topoisomerase Inhibitors / pharmacology*
Substances
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3-fluoro-6-methoxyquinoline
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Anti-Bacterial Agents
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Ether-A-Go-Go Potassium Channels
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Quinolines
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Topoisomerase II Inhibitors
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Topoisomerase Inhibitors
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DNA Topoisomerase IV
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DNA Gyrase