RESUMEN
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).
Asunto(s)
Antibacterianos/síntesis química , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Inhibidores de Topoisomerasa II , Aminas/química , Aminas/farmacología , Antibacterianos/química , Girasa de ADN , Bacterias Grampositivas/efectos de los fármacos , Concentración 50 Inhibidora , Quinazolinonas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Quinazolinonas/síntesis química , Topoisomerasa de ADN IV/antagonistas & inhibidores , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Inhibidores de Topoisomerasa IIRESUMEN
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.
