Síntese e avaliação das atividades : larvicida, antimicrobiana, ecotoxicológica e leishmanicida de derivados do ácido cinâmico

Abstract

Cinnamic acid and its natural or synthetic derivatives have numerous biological applications, such as: antineoplastic, inhibitory, antimicrobial, leishmanicidal, antioxidant, larvicidal and others. Their cinnamic structure is responsible for these therapeutic actions, as it has several reactive sites that contribute to the interaction with the associated target. In addition, DACs have low toxicity and can be used in cosmetics and food. These compounds are good candidates for combating neglected diseases, as they act on different mechanistic pathways. In addition, they can act against arthropods of the Aedes genus and multidrug-resistant pathogenic microorganisms, making them a strategy for controlling these target organisms. Thus, due to their diverse biological activities and because they come from natural sources, cinnamic acid and its derivatives have been used as a model for the synthesis of compounds with more effective insecticidal action. In this sense, this work reports on efficient methods for synthesizing DACs: Horner-Wadsworth-Emmons (HWE) olefination reaction, acid esterification, alkaline hydrolysis and Passerini (Multicomponent) reaction, respectively, obtaining n-substituted cinnamic compounds in good yields, in which six α acyloxycarboxyamides are new to the literature. The cinnamate derivatives and the α acyloxycarboxyamides were evaluated against the fourth instar larvae (L4) of Aedes aegypti, and those that showed moderate to active activity in the preliminary test were selected for LC50 determination. The in silico study carried out showed that ethyl p-chlorocinnamate, from the ethyl cinnamate series, scored best, corroborating its larvicidal activity result (LC50 = 8.3 µg/mL). Thus, ethyl p-chlorocinnamate was selected to identify and quantify the larval extract by means of HPLC analysis, as well as a morphological analysis of the larva under study. From the ecotoxicological study, it was possible to conclude that ethyl p-chlorocinnamate was not toxic to the plant species, and through HPLC analysis, the presence of p-chlorocinnamic acid was observed, suggesting enzymatic metabolization. This study was confirmed by the enzymatic inhibition of AChE present in the larval extract of the Aedes aegypti vector by the n substituted cinnamic esters, which had a larvicidal action. In addition, the esters and n substituted cinnamic acids were subjected to an antifungal study against Candida albicans and Cryptococcus neoformans, proving to be active with MIC’s ranging from 0, 24mM to 2.26mM, with ethyl (2E,4E)-5-phenylpenta-2,4-dienoate (0.24mM, SFD2) standing out against Candida albicans and p-chlorocinnamic acid (0.27mM) against Cryptococcus neoformans. The majority of the α-acyloxycarboxyamides showed low cytotoxicity in peritoneal macrophages (CC50> 400µM), making them of low toxicity. Furthermore, in the analysis of both promastigote and amastigote forms, it was found that the majority showed leishmanicidal activity, with the compounds SFD4 (CI50> 31.83µM and CI50 >27.28µM) and SFD10 (CI50> 33.88µM and CI50 >38.31µM) standing out, respectively. These, in turn, showed a good selectivity index (SI), being above the minimum allowed (SI>10), with SFD4 standing out with a SI > 14.66. Therefore, these results suggest that the DAC’s are good insecticide candidates and their structural scaffold can be used to design antifungal and leishmanicidal candidates.