Potencial farmacológico de novos complexos de Co(II) baseados em ligantes de tiocarbamoil-pirazolina como agentes antifúngicos

Abstract

Yeasts of the genus Candida have been a public health problem for many years, as they are associated with superficial and systemic infections in humans, and, in the last decades, developing resistance lesions and / or decreasing the allocation to antifungals used in tests. In view of the need for alternatives, a search for new antifungal drugs is the subject of current research for the treatment of invasive fungal infections. Thus, the present study aimed to evaluate two new Co (II) complexes with thiocarbamoyl-pyrazoline ligands as a possible drug for antifungal treatment. To assess pharmacological activity, antifungal, mutagenic and cytotoxic tests were performed. An antifungal activity of the complexes was evaluated by the powder microdilution method, in a 96-well microplate, using eight standard ATCC heads and six resistant clinical tests of Candida glabrata, using urine tests. Yeasts were tested with a range from 1.95 to 1000 μg mL-1 . A synergistic assessment of the complexes was tested with antifungal fluconazole by the chess method. Tests were carried out to evaluate biofilm inhibition and destruction in CIM, subCIM, 2.5xCIM, 5xCIM and 10xCIM and, subsequently, scanning electron microscopy for antibiofilm activity responses. To evaluate the mechanism of action of the complexes, sorbitol and ergosterol tests were performed. For the Ames test, concentrations between 50 and 5000 µg / plate were used against the strains TA98, TA100 and TA102 with and without metabolic activation. The same concentrations were used for the cytotoxicity assay by the MTS method against tumor cells (HeLa and SiHa) and non-tumor cells (Vero). The complexes showed antifungal activity in greater prominence for Candida glabrata ATCC 2001 CIM of 15.62 μg mL-1with fungistatic and fungicidal action. Among the clinical isolates of C. glabrata, the best biological action was for isolate 66, with activity of 3.90 μg mL-1 for complex 1 and 7.81 μg mL-1 for complex 2. For C. glabrata ATCC 2001 the complexes showed additive potential in combination with fluconazole. The complexes showed a percentage of biofilm inhibition of up to 90%. The complexes did not show mutagenic and cytotoxic potential at concentrations below 1500 μg mL-1 , this value being higher than the antifungal potential presented. By testing the mechanism of action of the complexes, it was possible to assess that both present activity in yeast ergosterol, thus, the complexes interfere with the cell membrane of these microorganisms. Thus, the complexes can be promising as a new drug for antifungal treatment.