RESUMEN
A library of 4,5- and 4,6-linked bivalent aminoglycoside (AMG) antibiotics consisting of neamine and nebramine pharmacophores have been synthesized. We probed the effect of the linker on antibiotic activity with a series of selected synthetic analogues with varied length and substituents. A number of compounds demonstrated in vitro activity against several bacterial strains and showed activity against drug resistant strains of Pseudomonas aeruginosa. Among the compounds prepared, analogues 12a-d were novel 4,6-linked AMGs containing the nebramine pharmacophore. In addition the lead compound OPT-11 possessed an ED(50) of Asunto(s)
Aminoglicósidos/química
, Aminoglicósidos/farmacología
, Antibacterianos/química
, Antibacterianos/farmacología
, Animales
, Evaluación Preclínica de Medicamentos
, Femenino
, Humanos
, Ratones
, Ratones Endogámicos BALB C
, Pruebas de Sensibilidad Microbiana
, Pseudomonas aeruginosa/efectos de los fármacos
, Pseudomonas aeruginosa/aislamiento & purificación
, Relación Estructura-Actividad
RESUMEN
Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6-position of nebramine provided a library of novel 4,6-linked aminoglycosides (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino, 2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant antimicrobial activity against Gram-(+) and -(-) bacteria. Several were particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL range.
