Avaliação da permeabilidade intestinal de derivados tiazolilhidrazona e tiazolilhidrazina com atividade antifúngica.

Abstract

Fungal infections are serious public health problem worldwide due to the high rates of morbidity and mortality. The arsenal of antifungal drugs is small and has several limitations, such as high toxicity, low oral bioavailability and limited antifungal spectrum. In addition, the emergence of fungal resistance and highly pathogenic species makes the situation even more critical and increases the demand for the discovery of new drugs. Given this scenario, the research group of Laboratório de Química Farmacêutica from Universidade Federal de Minas Gerais synthesized a series of thiazolylhydrazone and thiazolylhydrazine derivatives, and among them, two substances stood out for presenting high antifungal activity against several fungi, including the multidrug resistant species Candida auris. Therefore, this work aimed to evaluate the intestinal permeability of the thiazolylhydrazine PD76 and thiazolylhydrazone RJ44, by means of an in silico method, which correlates physicochemical properties of the molecules with their pharmacokinetic and toxicological characteristics, and in vitro assays, using the Caco-2 cell line. The quantification of the substances was performed by high performance liquid chromatography coupled to a diode array detector (HPLC-DAD), with methods validated according to RDC nº 27/2012 from ANVISA. The cytotoxicity of the substances was analyzed using the MTT method and the results indicate cell viability above 70% at the studied concentrations. PD76 showed an apparent permeability coefficient (Papp) of 5.25 x 10-6 cm/s, while RJ44 showed a Papp of 1.48 x 10-6 cm/s, both results indicating that the substances have moderate intestinal permeability. Furthermore, the evaluation of intestinal permeability using verapamil, a Pglycoprotein inhibitor, indicated that the efflux mechanism mediated by this transporter is significant in the RJ44 and PD76 permeation process. The results are promising and encourage the continuity of studies with these potential candidates for antifungal drugs.