RESUMEN
An allyl group was attached to 3-keto function of ketolides in the presence of allyl bromide and KOtBu. Consequently, the Heck reaction of the resulting 2, 3-dehydro-3-O-allyl-10, 11-anhydroclarithromycin derivatives, in the presence of palladium (II) acetate and tri(o-tolyl)phosphine, afforded a 3-O-(3-aryl-E-prop-2-enyl) sidechain, not the previously reported 3-O-(3-aryl-Z-prop-1-enyl) sidechain. The results suggested that some steric factors in ß-hydrogen elimination might regulate the isomerization. The activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives was low.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Claritromicina/farmacología , Antibacterianos/síntesis química , Claritromicina/análogos & derivados , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A facile and efficient route was presented to achieve 3-keto-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 8, 2,3-dehydro-3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 11, and 3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 12. Among them, compound 8, particularly 8d (Ar = 6-quinolyl), exhibited improved antibacterial activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and greatly enhanced activities against the resistant strains encoded by erm and mef genes, as compared to clarithromycin and azithromycin.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Éteres/química , Cetólidos/química , Cetólidos/farmacología , Antibacterianos/síntesis química , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Cetólidos/síntesis química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/genéticaRESUMEN
A series of novel 3-O-(3-aryl-propenyl)clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. Regioselective allylation at 3-OH was efficiently achieved in the presence of 9-oxime ether, compared with 9-keto. Most of the side chains were identified as the 3-O-(3-aryl-Z-prop-1-enyl) group, not the expected 3-O-(3-aryl-E-prop-2-enyl) group. Some derivatives of this series showed improved activities against erythromycin-resistant Staphylococcus aureus and Staphylococcus pneumoniae compared with the reference compound, clarithromycin, but weaker activities against susceptible strains.