Abstract
We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.
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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Cell Line, Tumor
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DNA Topoisomerase IV / antagonists & inhibitors
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / enzymology
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Organoselenium Compounds / chemical synthesis*
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Organoselenium Compounds / chemistry
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Organoselenium Compounds / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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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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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
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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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AVE6971
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Anti-Bacterial Agents
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Organoselenium Compounds
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Piperidines
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Quinolines
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Thiophenes
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Topoisomerase II Inhibitors
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DNA Topoisomerase IV