Síntese e avaliação da atividade citotóxica, leishmanicida e tripanocida de derivados nitroaromáticos

Abstract

In this work, a series of carboxylic acids and amides derived from 4-(bromomethyl)-3-nitrobenzoic acid was synthesized and evaluated as potential antitumoral, antileishmanial and trypanocidal agents. The carboxylic acid derivatives were obtained by radical bromination, electrophilic aromatic substitution and nucleophilic substitution reactions. The amides were synthesized from carboxylic acids and different amines using EDC as the coupling reagent. Conjugates of nitroaromatic unit and bioactive fatty acids (DHA and butyric acid) were synthesized in an attempt to optimize the activity of the compounds. The activity of the compounds was evaluated in vitro against three cancer cells lines (HL60 (leukemia), Jurkat (linfoma) and MCF-7 (breast cancer)), promastigotes forms of Leishmania amazonensis and amastigotes forms of Trypanosoma cruzi. In vitro cytotoxicity on the normal cells was evaluated using human peripheral blood mononuclear cells (PBMC). Among the compounds evaluated in the cytotoxic assay, the 4-(chloromethyl)-3-nitro-N-(2-hydroxyethyl)benzamide (4) was found to be the most active against HL60 (IC50 9.0 mM) and Jurkat (IC50 19.4 mM) cells lines. The amides 4-(bromomethyl)-3-nitro-N-(2-hydroxyethyl)benzamide (6) and N-(2-butanoyloxyethyl)-4-chloromethyl-3-nitrobenzamide (19) displayed significant activity against L. amazonensis (IC50 23.1 mM) and T. cruzi (IC50 13.9 mM), respectively. In a general way, the compounds showed low cytotoxicity to mammalian cells (PBMC)