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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Vaso, Carolina Orlando ; Bila, Niura Madalena ; Pandolfi, Fabiana ; De Vita, Daniela ; Bortolami, Martina ; Carvalho Bonatti, Jean Lucas ; de Moraes Silva, Rosangela Aparecida ; Carvalho Goncalves, Larissa Naiara ; Tudino, Valeria ; Costi, Roberta ; Di Santo, Roberto ; Soares Mendes-Giannini, Maria Jose ; Costa-Orlandi, Caroline Barcelos ; Scipione, Luigi ; Fusco-Almeida, Ana Marisa

• Tipo de documento: Artigo Científico
• Fonte: PHARMACEUTICS; v. 14, n. 5, p. 23-pg., 2022-05-01.

Resumo

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 mu g/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. (AU)

• Processo FAPESP: 20/15586-4 - Estabelecimento de um modelo tridimensional para determinação da eficácia e segurança farmacológica de derivados de nitrofuranos e indólicos e avaliação da infecção de Histoplasma capsulatum
• Beneficiário: Carolina Orlando Vaso
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/22188-8 - Avaliação da interação de biofilmes mono e dual-espécies de Candida spp e dermatófitos combinada a terapia fotodinâmica com 2-chalcona
• Beneficiário: Níura Madalena Bila
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/02785-9 - Dermatófitos e Dermatofitoses: formação de biofilme e desenvolvimento de estratégias de controle.
• Beneficiário: Maria José Soares Mendes Giannini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/18388-6 - O papel do biofilme na patogênese das dermatofitoses e desenvolvimento de estratégias de combate
• Beneficiário: Caroline Barcelos Costa Orlandi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/11836-0 - SELEÇÃO DE ALVOS TERAPÊUTICOS E/OU BIOMARCADORES A PARTIR DA RESPOSTA TRANSCRICIONAL GLOBAL DA INFECÇÃO DE MACRÓFAGOS ALVEOLARES POR BIOFILMES DE H. capsulatum
• Beneficiário: Ana Marisa Fusco Almeida
• Modalidade de apoio: Auxílio à Pesquisa - Regular