Síntese e correlação entre a estrutura e a atividade leishmanicida de novas amidas estiril-substituídas

Abstract

In this work describes the preparation of styryl-25 amides of which eight are new. The amides were obtained in good yields, by nucleophilic substitution reaction through formation of acid chlorides, by reacting styryl-substituted acids with the nucleophiles benzylamine, phenethylamine, 1,3-benzodioxolphenethylamine and 3,4-dimethoxiphenethylamine. Derivatives N-styryl-N,N'-dicyclo-hexyl-ureas were also obtained by coupling reaction with DCC. In addition, five compounds derivated from piperine, amide alkaloidal majority of Piper nigrum, were prepared, 4 of them new. The spectroscopic techniques IV and RMN 1H and 13C were used to characterize the products obtained. The bioavailability in aqueous medium for in vitro tests of styryl-substituted amides in three types of vehicles (EMS, PVP and -CD) was tested. The cytotoxicity of styryl-substituted amides for the promastigote form of Leishmania amazonensis and mouse macrophage cells was studied, as well as the enzyme inhibition against DNA topoisomerase II-  The antileishmanial tests showed that the series-styryl 5'-6'-dimetoxifenetilamidas was the most cytotoxic, showing a higher selectivity for the macrophages. The series of styryl-benzyl and phenethyl-amide showed linear correlations between the logP values and % inhibition against L. amazonensis at a concentration of 50 M. It was observed that, in general, vehicles CD and PVP contributed to the bioavailability of amides regardless of the electronic effect of the substituent. The styryl-amides, for the most part, inhibited the enzymatic activity of topoisomerase II-.