Planejamento e síntese de derivados tiazolilhidrazonas como potenciais antifúngicos.

Abstract

Fungal infections are an emergent issue in the sanitary community. Estimates from 2017 state that more than one billion people present a mycosis, whilst 150 million cases of them are invasive infections and are considered serious comorbidities. These infections result in two million deaths per year. Another concern relies on the multidrug resistance presented by some fungal strains, leading to an urgency in the discovery of novel antifungal classes as therapeutical alternatives for the treatment of these type of infections. A promising chemical skeleton to develop new antifungals is the 2-thiazolylhydrazone scaffold, which presents potent bioactivity, especially against Candida and Cryptococcus species. In this work, we aimed to design and synthesize 2-thiazolylhydrazone derivatives as potential antifungal agents. Machine learning-based classifications models were constructed and validated for the prediction of antifungal activity of 2-thiazolylhydrazones. The species Candida albicans and Cryptococcus neoformans were selected as representatives for each genus. The six most robust models (three for each fungus), according to the statistical parameters, were selected for a virtual screening protocol. They were applied to classify two virtual chemical libraries with >175 thousand molecules. The six models, in a consensus, selected 486 compounds as potential antifungal agents against both fungi. Another filter based on lipophilicity and water solubility was applied to define the analogs to be synthesized with probable good oral bioavailability. Electronic and molecular properties were calculated for two 2-thiazolylhydrazones (63 and 72) previously studied regarding their stabilities in aqueous medium, as well as for other five analogs (62, 78, 96, 121, and 123), aiming to stablish a relationship between those properties with hydrolysis potential of the hydrazone moiety. According to the results, the electrostatic charges and the calculated energies for the frontier orbitals could be related to the experimental results for X-Y, thus it has been able to extend this interpretation for the five analogs to predict the possible hydrolysis. Four thiosemicarbazone intermediates (TS2-TS5) were obtained with 61-100% yield. They lead to the synthesis of 18 2-thiazolylhydrazones (TH2a-h, TH3a, TH4a-h, and TH5a) after a condensation reaction with α-haloketones, with 41-93% yield. Also, another four 2-thiazolylhydrazines (TH6a-d) were obtained with 25-59% yield. The biological activity of the synthesized compounds was assessed in vitro using broth microdilution assay against four Candida species (C. albicans, C. auris, C. krusei, and C. tropicalis). Five 2-thiazolylhydrazones showed MIC values lower than 10 µmol/L against one of the species, at least (TH2h, TH3a, TH4e-f, and TH5a). The four 2-thiazolylhydrazines showed MIC < 10 µmol/L.