Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida

Abstract

In recent years there has been an increase in the incidence of diseases resulting from fungal infection, currently prevailing as an important factor of morbidity and mortality in humans. Fungal resistance to pharmacological therapy has been observed in several species, especially in the genus Candida. Thus, the search for new drug candidates is important for the development of more effective drugs. Therefore, the present study aimed to prepare and evaluate the pharmacological activity of thirteen benzoxazole and benzothiazole derivatives through in vitro studies, with the perspective of obtaining biologically active compounds and investigating chemical parameters relevant to bioactivity. The compounds were prepared by means of the decarboxylation coupling of cinnamic acid derivatives with a coupler reagent and were structurally characterized by spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of Hydrogen and Carbon Thirteen and High Resolution Mass Spectrometry. Among the products obtained, six compounds are unprecedented. Subsequently, the antifungal assays were performed by determining the minimum inhibitory concentration (MIC) and the minimum fungicide concentration (MFC). In addition, the mechanism of action (sorbitol and ergosterol) against C. albicans was investigated, in which it was evidenced that the antifungal action occurs targeting the plasma membrane. The CFM/MIC ratio determined that compounds 3, 6 and 7 have fungistatic activity (CFM/MIC 4), while the other compounds exert fungicidal activity (CFM/MIC 4) ≥<for the species evaluated. All compounds showed activity at the tested concentrations (1000 to 7.81 μg/mL). 2-benzyl-5-methylbenzo[d]xazole (1) showed strong bioactivity against C. krusei with MIC of 69.9 μM (15.6 μg/mL), moderate against C. albicans and weak against C. tropicalis, with MIC of 279.9 μM (62.6 μg/mL) and 559.8 μM (125.0 μg/mL), respectively. The 2-(2-fluorobenzyl)-5-methylbenzo[d]xazole (2) in turn showed moderate bioactivity with MIC equal to 250.0 μM (62.5 μg/mL) against C. krusei and showed weak activity against C. albicans and C. tropicalis with MIC of 1036.9 μM (250.0 μg/mL). The analysis of the structure-activity relationship of compounds 1-5, all with a methyl bound to carbon 5 of the benzoxazole nucleus, showed that the insertion of substituent groups in the benzyl ring reduces the pharmacological potency. Benzoazoles 6-9, with no substitution in the benzothiazole ring, and benzoxazoles 10-13, with a chlorine atom attached to carbon 5 of the benzoxazole nucleus, also exhibited bioactivity ranging from very weak to weak, regardless of the substitutions in the benzyl ring. In general, bioactive compounds may represent an important starting point in the future planning of new antifungal drug candidates.