(-)-Carveol: atividade antifúngica sobre Sporothrix brasiliensis, citotoxicidade, ADMET e docking molecular

Abstract

Sporotrichosis is a subcutaneous fungal infection caused by fungi belonging to the clinical clade of Sporothrix. It is considered an endemic disease in Brazil, representing a significant public health issue. The fungus has saprophytic characteristics, meaning it is commonly found in soil and decomposing organic matter. In recent years, zoonotic transmission has been observed as the primary form of transmission, consisting of the transmission of fungal propagules from animals to humans or other animals. This form favors high presence of S. brasiliensis among humans, being the most prevalent species in the country. Current treatment options are scarce, with the main ones being saturated potassium iodide solution, itraconazole, terbinafine, and amphotericin B, which, as primary concerns, express adverse effects and toxicity in some cases. Factors such as the increase in antifungal-resistant strains, the cost and prolonged duration of treatment, and adverse effects have driven the search for new substances with antifungal activity, and medicinal plants and their phytoconstituents have been widely investigated in this regard. Thus, the objective of this study was to investigate the antifungal activity of the monoterpene (-)-Carveol, identify molecular targets, its drug interaction with reference antifungals, visualize its action in the fungal cell, and analyze its toxicity. To analyze the antifungal activity of (-)-Carveol against S. brasiliensis, the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) were determined, along with interaction analysis with sorbitol and ergosterol, and the effect of its combination with other drugs was analyzed. In addition, its cytotoxicity in human keratinocyte (HaCaT) was evaluated, along with an in silico analysis of the pharmacokinetic and toxicological properties ADMET (absorption, distribution, metabolism, excretion, and toxicity) to predict the behavior of chemical bonds through molecular docking. (-)-Carveol showed an MIC of 256 μg/mL on the majority of strains tested, with fungicidal characteristics. The results suggest that this activity does not occur on the fungal cell wall nor through the complexation of the monoterpene with the ergosterol of the fungal membrane. The association of (-)-Carveol with itraconazole showed an antagonistic effect. Cell viability remained above 50% at concentrations of 256 μg/mL and 512 μg/mL in the tested cell line. In the in silico studies, (-)-Carveol presented a low probability of pharmacokinetic drug interactions and toxicity, better distribution in tissues and plasma when compared to itraconazol; as well as not being hepatotoxic and showing no risks of mutagenicity or tumorigenicity, which are characteristics presented by itraconazole. Both (-)-Carveol and itraconazole interact by binding to the active site of CYP51, but itraconazole showed binding priority and greater affinity for the binding site. This study demonstrates that (-)-Carveol exhibits potential antifungal activity and may serve as an alternative for the treatment of sporotrichosis and the control of fungal dissemination. Further studies are needed to identify its mechanism of action and explore strategies to improve its cytotoxicity profile.