RESUMO
A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).
Assuntos
Antibacterianos/síntese química , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Inibidores da Topoisomerase II , Aminas/química , Aminas/farmacologia , Antibacterianos/química , DNA Girase , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-AtividadeRESUMO
The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Quinazolinonas/síntese química , DNA Topoisomerase IV/antagonistas & inibidores , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores da Topoisomerase IIRESUMO
A series of 3-hydroxyquinazoline-2,4-diones was synthesized and evaluated for antibacterial activity. This series represents a novel addition to the DNA gyrase inhibitor class of antibacterials. Appropriate substitutions onto the core template yielded compounds with excellent potency against E. coli gyrase and significant in vitro Gram-negative and Gram-positive antibacterial activity.