RESUMEN
A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.
Asunto(s)
Antibacterianos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Quinazolinonas , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Técnicas Químicas Combinatorias , Fluoroquinolonas/síntesis química , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinazolinonas/síntesis química , Quinazolinonas/química , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
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.