Evaluation of the Anti-<i>Histoplasma capsulatum</i> Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures
Carolina Orlando Vaso,
Níura Madalena Bila,
Fabiana Pandolfi,
Daniela De Vita,
Martina Bortolami,
Jean Lucas Carvalho Bonatti,
Rosângela Aparecida De Moraes Silva,
Larissa Naiara Carvalho Gonçalves,
Valeria Tudino,
Roberta Costi,
Roberto Di Santo,
Maria José Soares Mendes-Giannini,
Caroline Barcelos Costa-Orlandi,
Luigi Scipione,
Ana Marisa Fusco-Almeida
Affiliations
Carolina Orlando Vaso
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Níura Madalena Bila
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Fabiana Pandolfi
Department of Scienze di Base e Applicate per l’Ingegneria, Sapienza University of Rome, Via Castro Laurenziano 7, 00185 Rome, Italy
Daniela De Vita
Department of Environmental Biology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Martina Bortolami
Department of Scienze di Base e Applicate per l’Ingegneria, Sapienza University of Rome, Via Castro Laurenziano 7, 00185 Rome, Italy
Jean Lucas Carvalho Bonatti
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Rosângela Aparecida De Moraes Silva
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Larissa Naiara Carvalho Gonçalves
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Valeria Tudino
Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Roberta Costi
Department of Chemistry and Technology of Drug, Istituto Pasteur, Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Roberto Di Santo
Department of Chemistry and Technology of Drug, Istituto Pasteur, Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Maria José Soares Mendes-Giannini
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Caroline Barcelos Costa-Orlandi
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Luigi Scipione
Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Ana Marisa Fusco-Almeida
Department of Clinical Analysis, School of Pharmaceutical Science, Universidade Estadual Paulista, Araraquara 14800-903, SP, Brazil
Histoplasma capsulatum 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 H. capsulatum EH-315 strain. Compounds with a minimum inhibitory concentration (MIC90) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC90 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 7, 11, and 32. These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, 7 and 11 damaged the cell wall, causing flaws in the contour (11), or changing the size and shape of the fungal cell wall (7). Furthermore, 7 and 32 induced reactive oxygen species (ROS) formation higher than 11 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.