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

Department of Chemistry and Technology of Drug, Istituto Pasteur, Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy

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Academic Editor: Clive Prestidge

Pharmaceutics 2022, 14(5), 1043; https://doi.org/10.3390/pharmaceutics14051043

Received: 7 April 2022 / Revised: 4 May 2022 / Accepted: 9 May 2022 / Published: 12 May 2022

(This article belongs to the Special Issue Recent Advances in Antifungal Drugs)

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Abstract

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. View Full-Text

Keywords: Histoplasma capsulatum; three-dimensional models; nitrofurans; indoles; pharmacological replacement; mechanisms of action; cytotoxicity; antifungal activity; drug repositioning; spheroids

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MDPI and ACS Style

Vaso, C.O.; Bila, N.M.; Pandolfi, F.; De Vita, D.; Bortolami, M.; Bonatti, J.L.C.; De Moraes Silva, R.A.; Gonçalves, L.N.C.; Tudino, V.; Costi, R.; Di Santo, R.; Mendes-Giannini, M.J.S.; Costa-Orlandi, C.B.; Scipione, L.; Fusco-Almeida, A.M. Evaluation of the Anti-Histoplasma capsulatum Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures. Pharmaceutics 2022, 14, 1043. https://doi.org/10.3390/pharmaceutics14051043

AMA Style

Vaso CO, Bila NM, Pandolfi F, De Vita D, Bortolami M, Bonatti JLC, De Moraes Silva RA, Gonçalves LNC, Tudino V, Costi R, Di Santo R, Mendes-Giannini MJS, Costa-Orlandi CB, Scipione L, Fusco-Almeida AM. Evaluation of the Anti-Histoplasma capsulatum Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures. Pharmaceutics. 2022; 14(5):1043. https://doi.org/10.3390/pharmaceutics14051043

Chicago/Turabian Style

Vaso, Carolina O., Níura M. Bila, Fabiana Pandolfi, Daniela De Vita, Martina Bortolami, Jean L.C. Bonatti, Rosângela A. De Moraes Silva, Larissa N.C. Gonçalves, Valeria Tudino, Roberta Costi, Roberto Di Santo, Maria J.S. Mendes-Giannini, Caroline B. Costa-Orlandi, Luigi Scipione, and Ana M. Fusco-Almeida. 2022. "Evaluation of the Anti-Histoplasma capsulatum Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures" Pharmaceutics 14, no. 5: 1043. https://doi.org/10.3390/pharmaceutics14051043

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

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