Abstract
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
MeSH terms
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Animals
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Anti-Bacterial Agents / administration & dosage
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Bacterial Outer Membrane Proteins / antagonists & inhibitors*
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Drug Evaluation, Preclinical
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Drug-Related Side Effects and Adverse Reactions
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Female
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Haplorhini
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Infusions, Intravenous
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Male
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Membrane Transport Proteins
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Microbial Sensitivity Tests
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Molecular Structure
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology*
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Pseudomonas Infections / drug therapy*
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Pseudomonas aeruginosa / drug effects*
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Quaternary Ammonium Compounds / administration & dosage
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Quaternary Ammonium Compounds / chemical synthesis
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Quaternary Ammonium Compounds / chemistry
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Quaternary Ammonium Compounds / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Solubility
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Stereoisomerism
Substances
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Anti-Bacterial Agents
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Bacterial Outer Membrane Proteins
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D13-9001
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Membrane Transport Proteins
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MexA protein, Pseudomonas aeruginosa
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MexB protein, Pseudomonas aeruginosa
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OprM protein, Pseudomonas aeruginosa
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Piperidines
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Quaternary Ammonium Compounds