RESUMEN

Fourteen 5-nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides (3a-n) were synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)), as well as their cytotoxicity and MTB isocitrate lyase (ICL) inhibition activity. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl)-4-[(5-nitro-2,6-dioxohexahydro-4-pyrimidinyl)carbonyl]piperazino-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3n) was found to be the most active compound in vitro with MICs of < 0.17 and 0.17 µM against log-phase MTB and MDR-TB, respectively. Some compounds showed 20-45% inhibition against MTB ICL at 10 µM.

Asunto(s)

Antibacterianos/síntesis química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Isocitratoliasa/antagonistas & inhibidores , Mycobacterium/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Chlorocebus aethiops , Simulación por Computador , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Isocitratoliasa/química , Isocitratoliasa/metabolismo , Ligandos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium/crecimiento & desarrollo , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/crecimiento & desarrollo , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Piperazinas , Unión Proteica , Pirimidinas/química , Pirimidinas/metabolismo , Quinolinas , Tuberculosis/tratamiento farmacológico , Células Vero