RESUMEN
SAR studies and optimization of various modified Hygromycin A fluoroalkyl ethers, which led to the discovery of the highly potent 4'-(2-cyclopropyl-2-fluoroethyl ether) antibacterial CE-156811 (1) derived from truncation of the ribose ring and difluorination of the phenyl found in Hygromycin A, are discussed.
Asunto(s)
Antibacterianos/química , Cinamatos/química , Dioxoles/química , Higromicina B/análogos & derivados , Administración Oral , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Haplorrinos , Higromicina B/química , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Relación Estructura-ActividadRESUMEN
We evaluated a novel truncated hygromycin A analog in which the furanose ring was replaced with a 2-fluoro-2-cyclopropylethyl substituent for its activity against multidrug resistant gram-positive bacteria and compared its activity to the activities of linezolid, quinupristin-dalfopristin, and vancomycin. CE-156811 demonstrated robust in vitro activity against gram-positive bacteria that was comparable to that of linezolid.
Asunto(s)
Antibacterianos/farmacología , Cinamatos/farmacología , Dioxoles/farmacología , Bacterias Grampositivas/efectos de los fármacos , Higromicina B/análogos & derivados , Acetamidas/farmacología , Antibacterianos/química , Cinamatos/química , Dioxoles/química , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/aislamiento & purificación , Bacterias Grampositivas/aislamiento & purificación , Humanos , Higromicina B/química , Higromicina B/farmacología , Técnicas In Vitro , Linezolid , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/farmacologíaRESUMEN
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.