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
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Cinamatos/síntesis química , Cinamatos/farmacología , Higromicina B/análogos & derivados , Higromicina B/síntesis química , Higromicina B/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
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.