RESUMEN

A series of aminophenylhydroxamates and aminobenzylhydroxamates were synthesized and screened for their antiparasitic activity against Leishmania, Trypanosoma, and Toxoplasma. Their anti-histone deacetylase (HDAC) potency was determined. Moderate to no antileishmanial or antitrypanosomal activity was found (IC50 > 10 µM) that contrast with the highly efficient anti-Toxoplasma activity (IC50 < 1.0 µM) of these compounds. The antiparasitic activity of the synthetized compounds correlates well with their HDAC inhibitory activity. The best-performing compound (named 363) express a high anti-HDAC6 inhibitory activity (IC50 of 0.045 ±â€¯0.015 µM) a moderate cytotoxicity and a high anti-Toxoplasma activity in the range of known anti-Toxoplasma compounds (IC50 of 0.35-2.25 µM). The calculated selectivity index (10-300 using different human cell lines) of the compound 363 makes it a lead compound for the future development of anti-Toxoplasma molecules.

Asunto(s)

Antiparasitarios/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/efectos de los fármacos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Antiparasitarios/síntesis química , Línea Celular , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/aislamiento & purificación , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Leishmania/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Toxoplasma/efectos de los fármacos , Trypanosoma/efectos de los fármacos