Explorando o potencial antifúngico e antiparasitário de salicilatos e salicinamidas

Abstract

Neglected diseases affect almost two billion people in the world, with Brazil being one of the most affected countries due to the high prevalence of these pathologies. In addition, Candida infections are a cause for concern due to increased microbial resistance to antifungals. Therefore, it is essential to search for new drug candidates for the treatment of these infections. The present study aimed to prepare and evaluate the antiparasitic and antifungal activity of a collection of salicylic acid derivatives. The collection of twenty-five compounds derived from salicylic acid were prepared using the Fischer esterification reaction, Mitsunobu reaction, nucleophilic substitution reaction with alkyl halide and Schotten-Baumann reaction, obtaining six new products. The structures of the synthetic derivatives were characterized by infrared spectroscopy, 1H and 13C NMR, DEPT 135 and high resolution mass spectrometry. The compounds were subjected to biological evaluation against species of the genus Candida and twelve derivatives evaluated in vitro against Leishmania braziliensis, Trypanosoma cruzi and Plasmodium falciparum. To investigate the antifungal activity, the broth microdilution method was used to determine the minimum inhibitory concentration (MIC) and verify the probable mechanism of antifungal action of the compound with the best bioactivity. The compound with the best antifungal profile was N-cyclohexyl-2-hydroxybenzamide (15) with an MIC of 125 μg/mL against C. albicans ATCC 90028, C. albicans CBS 5602 and C. krusei CBS 573; and MIC = 250 μg/mL against C. tropicalis CBS 94, suggesting that salicylamide with a six-membered aliphatic ring can enhance this bioactivity. In the study of the mode of action on the membrane or fungal cell wall of 15, it was observed that the compound does not interact directly with the ergosterol present in the plasma membrane or with the fungal cell wall, which shows that its mechanism of action is through other biological targets. While in silico analysis suggested a multi-target antifungal mechanism of action. The cytotoxic activity of the twelve compounds was evaluated by the viability of the human promonocytic cell line U-937 (ATCC CRL-1593.2TM) via the MTT method. The trypanocidal, leishmanicidal and antiplasmodial assay was carried out against the epimastigote forms of T. cruzi, in intracellular amastigotes of L. braziliensis and asynchronous cultures of P. falciparum 3D7, respectively, with determination of the EC50 of the compounds. In general, the compounds evaluated showed high LC50 values in the cytotoxicity assay and low antiparasitic activity. The data demonstrated in this study can be used in future research into the development of products with potential antiparasitic and antifungal bioactivity.