RESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Piperidinas/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Haplorrinos , Infusiones Intravenosas , Masculino , Proteínas de Transporte de Membrana , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Compuestos de Amonio Cuaternario/administración & dosificación , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/química , Ratas , Ratas Sprague-Dawley , Solubilidad , EstereoisomerismoRESUMEN
A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized 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. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Carbono/química , Carbono/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Modelos Químicos , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Concentración 50 Inhibidora , Proteínas de Transporte de Membrana , Pruebas de Sensibilidad MicrobianaRESUMEN
Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Farmacorresistencia Bacteriana/efectos de los fármacos , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Acrilatos/farmacología , Estabilidad de Medicamentos , Isomerismo , Pruebas de Sensibilidad Microbiana , Fotoquímica , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
