Assuntos
Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Aminoglicosídeos/síntese química , Antibacterianos/síntese química , Sequência de Carboidratos , Dimerização , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
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 Assuntos
Aminoglicosídeos/química
, Aminoglicosídeos/farmacologia
, Antibacterianos/química
, Antibacterianos/farmacologia
, Animais
, Avaliação Pré-Clínica de Medicamentos
, Feminino
, Humanos
, Camundongos
, Camundongos Endogâmicos BALB C
, Testes de Sensibilidade Microbiana
, Pseudomonas aeruginosa/efeitos dos fármacos
, Pseudomonas aeruginosa/isolamento & purificação
, Relação Estrutura-Atividade
RESUMO
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.