RESUMEN

Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.

Asunto(s)

Antibacterianos/síntesis química , Azitromicina/síntesis química , Macrólidos/síntesis química , Microsomas Hepáticos/efectos de los fármacos , Infecciones Neumocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/farmacocinética , Azitromicina/análogos & derivados , Azitromicina/farmacocinética , Disponibilidad Biológica , Ácidos Carboxílicos/química , Cristalografía por Rayos X , Estabilidad de Medicamentos , Ésteres/química , Humanos , Inyecciones Intravenosas , Macrólidos/farmacocinética , Masculino , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Infecciones Neumocócicas/microbiología , Ratas , Ratas Wistar , Streptococcus pneumoniae/crecimiento & desarrollo