RESUMEN
Cephalosporins with new aminobenzimidazole and aminoimidazoline heterocycles at C-7 have been synthesized starting with versatile C-7 isocyanide dihalide synthons. The aminobenzimidazoles have a broad spectrum of antibacterial activity, including Gram-positive and Gram-negative organisms, but possess limited beta-lactamase stability. In contrast, the aminoimidazolines have a narrow spectrum of antibacterial activity, limited to Gram-negative strains only, but possess outstanding beta-lactamase stability. Structure-activity relationships are discussed in terms of their dependence on the pKa of the C-7 amino heterocycle, basic C-7 residues giving cephalosporins with exceptional beta-lactamase stability.
Asunto(s)
Bacterias/efectos de los fármacos , Cefalosporinas/química , Compuestos Heterocíclicos , Imidazoles , beta-Lactamasas/metabolismo , Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Fenómenos Químicos , Química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Cephalosporins with new catechol substituents at C-3' have been synthesized, including novel compounds with C-3' carbon-carbon bonds. Many of these compounds have high potency against Gram-negative bacteria, in particular against resistant strains like Pseudomonas aeruginosa. Structure-activity relationships are discussed in terms of their dependence on the pKa of the C-3' catechol and also in terms of steric and conformational factors of the C-3' substituent. The best overall properties were found in compounds with a bulky and/or conformationally restricted acidic C-3' catechol.
Asunto(s)
Cefalosporinas/síntesis química , Animales , Proteínas Sanguíneas/metabolismo , Callithrix , Catecoles/síntesis química , Catecoles/farmacología , Cefalosporinas/farmacocinética , Cefalosporinas/farmacología , Estabilidad de Enzimas , Femenino , Masculino , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Relación Estructura-Actividad , beta-Lactamasas/metabolismoRESUMEN
Cephalosporins with new aminoimidazole heterocycles at C-7 have been synthesized by reaction of anti-alpha-aminooximes with C-7 dihaloisocyanocephalosporins esters or by direct condensation of 2-fluoroimidazoles with C-7 aminocephalosporins esters. These compounds combine a broad spectrum of antibacterial activity, including Gram-negative and Gram-positive organisms with a good beta-lactamase stability. Activity is discussed in terms of its relationship to the pKa of the C-7 aminoimidazole heterocycle, basic C-7 aminoimidazole residues gave cephalosporins with the best beta-lactamase stability but the poorest activity against Gram-positive organisms. An additional interesting property of the C-7 imidazolylaminocephalosporins is the oral activity present in some compounds of this series.