Abstract
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 μM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 μM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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DNA Topoisomerases, Type II / metabolism*
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Dogs
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Drug Resistance, Bacterial
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Gram-Negative Bacteria / drug effects
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Gram-Positive Bacteria / drug effects
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Mice
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Microbial Sensitivity Tests
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Models, Molecular
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Protein Conformation
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Rats
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Staphylococcal Infections / drug therapy
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Structure-Activity Relationship
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Topoisomerase Inhibitors / chemical synthesis*
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Topoisomerase Inhibitors / pharmacokinetics
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Topoisomerase Inhibitors / pharmacology
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Piperidines
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Topoisomerase Inhibitors
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DNA Topoisomerases, Type II