RESUMEN
A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure-activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development.
Asunto(s)
Benzamidas/química , Benzamidas/síntesis química , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/química , Pirimidinas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Benzamidas/farmacocinética , Benzamidas/toxicidad , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Semivida , Inhibidores de Histona Desacetilasas/farmacocinética , Inhibidores de Histona Desacetilasas/toxicidad , Histona Desacetilasas/metabolismo , Humanos , Células MCF-7 , Pirimidinas/farmacocinética , Pirimidinas/toxicidad , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel bis-aryl ureas containing trifluoromethyl imidazolyl group targeting Raf kinase were designed and synthesized based on the lead compound of Sorafenib. All the prepared compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines including MDA-MB-231 (breast), BGC-823 (gastric), and SMMC-7721 (liver). Several compounds from the series exhibited excellent antitumor activities against all three tested cancer lines. Further their inhibitory activities against Raf kinase were investigated, and three compounds (11c, 11d, and 11p) demonstrated better activities than contrast drug Sorafenib. Especially compound 11c was found to be a potent and selective Raf kinase inhibitor and could be considered as a candidate compound for further development.