Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos

Abstract

In recent years there has been an increase in studies on fungi, due to the high incidence of diseases caused by them, demonstrating that today these microorganisms are important causes of mortality in humans, reaching millions of people per year in the world. Due to the indiscriminate use of drugs indicated for the treatment of candidiasis, the occurrence of fungal resistance is observed, requiring the development of new pharmacotherapeutic alternatives. Phenolic acids, such as sinapic acid, constitute groups of aromatic carboxylic acids widely found in plants, which present structural diversity and several described biological activities, with emphasis on antimicrobial activity, such as the anti-Candida action. Thus, the present study aimed to prepare a collection of eleven synapates (1-11), structurally related, and to evaluate the antifungal activity of these compounds against two species of fungi, C. albicans and C. tropicalis, and to establish the structure-activity relationship of the substances evaluated. Synthetic derivatives were prepared via Fischer esterification, Steglich reaction, and esterifications with aryl halides in the presence of triethylamine. In the structural characterization, the spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of 1H and 13C were used. Products were obtained in yields of 13.9–82.3%. Among the eleven compounds obtained, six are unpublished in the literature (5, 7-11). The antifungal test was performed by determining the minimum inhibitory concentration (MIC) and establishing the minimum fungicidal concentration (CFM), including the investigation of the mechanism of action (sorbitol and ergosterol). When analyzing the results, it can be seen that esters 4, 5 and 8 showed a fungicidal effect with values of MIC = CFM = 213.8 μM and 53,4 μM, MIC = CFM = 25.3 μM and 25.3 μM, MIC = CFM = 43.8 μM and 175,3 μM against C. albicans and C. tropicalis, respectively. It was found through the ratio (CFM/MIC<4), that the molecules exerted a fungicidal effect. Regarding the structural characteristics of the esters on the antifungal bioactivity, the importance of the medium alkyl chains and the aryl substituent with a large alkyl group in the para position of the ring was evidenced. According to the ergosterol test it is suggested that the mechanism of action occurs in the plasma membrane of the fungal cell. The in silico analysis on pharmacokinetic and toxicological prediction suggested that the compounds are not lethal, carcinogenic and multagenic, with 1 and 3 being hepatotoxic and immunotoxic, while the others showed only cytotoxicity. As for absorption, all showed good water solubility, which indicates that they can be administered orally. Therefore, it was possible to establish chemical characteristics that can serve as a reference for the advancement in the development of new antifungal compounds with better biological action against Candida species.