Evaluation of the Anti- Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures.

is a fungus that causes histoplasmosis. The increased evolution of microbial resistance and the adverse effects of current antifungals help new drugs to emerge. In this work, fifty-four nitrofurans and indoles were tested against the EH-315 strain. Compounds with a minimum inhibitory concentration (MIC) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC on ATCC G217-B strain and their minimum fungicide concentration (MFC) on both strains. The quantification of membrane ergosterol, cell wall integrity, the production of reactive oxygen species, and the induction of death by necrosis-apoptosis was performed to investigate the mechanism of action of compounds , , and . These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, and damaged the cell wall, causing flaws in the contour (), or changing the size and shape of the fungal cell wall (). Furthermore, and induced reactive oxygen species (ROS) formation higher than and control. Finally, the cytotoxicity was measured in two models of cell culture, i.e., monolayers (cells are flat) and a three-dimensional (3D) model, where they present a spheroidal conformation. Cytotoxicity assays in the 3D model showed a lower toxicity in the compounds than those performed on cell monolayers. Overall, these results suggest that derivatives of nitrofurans and indoles are promising compounds for the treatment of histoplasmosis.