Abstract
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.
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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Aztreonam / chemistry
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Aztreonam / pharmacology
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Bacterial Outer Membrane Proteins / antagonists & inhibitors*
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Levofloxacin
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Lung / drug effects
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Lung / microbiology
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Membrane Transport Proteins
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Microbial Sensitivity Tests
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Ofloxacin / chemistry
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Pseudomonas aeruginosa / drug effects*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
Substances
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Anti-Bacterial Agents
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Bacterial Outer Membrane Proteins
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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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Pyrimidines
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Levofloxacin
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Ofloxacin
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Aztreonam