Reposicionamento de fármacos para o tratamento de criptococose

Abstract

Cryptococcosis is a systemic mycosis caused by yeasts of the genus Cryptococcus, mainly by the species Cryptococcus neoformans and Cryptococcus gattii. The therapeutic alternatives currently available for the treatment of the disease are scarce, have high toxicity, high cost and limited accessibility. In this sense, drug repositioning (RF), a strategy that consists of researching new therapeutic applications for drugs or drug candidates, constitutes a promising approach for the discovery of new alternatives for the treatment of cryptococcosis.Therefore, the objective of the present work was to evaluate the antifungal potential of drugs with privileged structures (PE) for repositioning in the treatment of cryptococcosis.For that, a library with 28 drugs with PE was created and evaluated against strains of C. neoformans and C. gattii. The drugs albendazole (ALB), duloxetine (DUL), fenbendazole (FEM), flubendazole (FLU), mebendazole (MEB) and paroxetine (PAR) showed promising anticryptococcal activity, with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (CFM). ) between 0.047 µM and 100 µM. When evaluated in combination with fluconazole (FLZ) against C. neoformans ATCC H99, none of the drugs in the library showed a fractional inhibitory concentration index (CIIF) ≤ 0.5, therefore, no synergism was observed. However, additive effects were observed for the combinations of FLZ with FIN, HID and PAR with ICIF equal to 1 for the three drugs. The combinations and FLZ+FIN, FLZ+HID AND FLZ+PAR were analyzed by the reference models of Bliss, Loewe, HSA and ZIP, which suggest additive effects for the combinations. A post-antifungal effect (PAFE) was observed for the MIC of the drugs ALB, DUL, FEM, FLU, MEB and PAR between 3.5 and 10.5 hours, as well as for the additive combinations FLZ+FIN, FLZ+HID and FLZ +PAR with PAFE between 12 and 22.5 hours. Besides that, for all evaluated drugs, it was possible to observe significant morphological impacts with reduced cell diameter and capsule size in C. neoformans ATCC H99 after treatment with subinhibitory concentrations.