title: Effects of two 6-quinolinyl chalcones on the integrity of plasma membrane of Paracoccidioides brasiliensis.
abstract: Paracoccidioidomycosis is the most prevalent systemic mycosis in Latin America, yet few therapeutic options exist. Our aim was to search for new compounds with high efficacy, low toxicity, shorter treatment time and affordable cost. We studied two synthetic 6-quinolinyl chalcones, 3b and 3e, to determine their effects on VERO cells, antifungal activity, survival curve, interaction with other drugs and phenotypic effects against several isolates of Paracoccidioides spp. In this study, we verified that the compounds were not toxic, exhibited superior in vitro activity compared with that shown by trimethoprim-sulfamethoxazole, and after 5 days of treatment, decreased the fungal cell viability by approximately 70%. Additionally, no interactions were observed between the tested compounds and other drugs. We also found that these compounds induced morphological changes, such as shriveling of cells, fragmentation of the plasma membrane and cytoplasmic disorganization in vitro. The changes observed by microscopy assays corroborate the observation made with propidium iodide, where the number of cells stained with the compounds was higher than that observed after amphotericin B treatment. We observed an increase in the efflux of K+and a loss of intracellular contents in cells treated with 3b and 3e, confirming their effects on fungal membranes. However, damage to the membrane was not associated with a decrease in membrane ergosterol levels. The experimental evidences showed no direct indications of cellular wall damage caused by these compounds. Thus, these results confirm the antifungal potential of 3b and 3e against Paracoccidioides spp. with possible action on the membrane.
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Nívea P
authors.initials: NP
authors.lastname: de Sá
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Cisalpino
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Luciana C
authors.initials: LC
authors.lastname: Tavares
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Espíndola
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Beatriz M
authors.initials: BM
authors.lastname: Borelli
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Paulo Js
authors.initials: PJ
authors.lastname: Barbeira
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Gabriele de Matos
authors.initials: GM
authors.lastname: Cardoso Perdigão
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rosa
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Moacir G
authors.initials: MG
authors.lastname: Pizzolatti
authors.affiliation: Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, MG, Brazil.
authors.forename: Susana
authors.initials: S
authors.lastname: Johann
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000187:drug effects / Q000648:ultrastructure; D004875:Ergosterol / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010228:Paracoccidioides / Q000187:drug effects* / Q000648:ultrastructure; D010229:Paracoccidioidomycosis / Q000382:microbiology; D011188:Potassium / Q000378:metabolism; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000935:Antifungal Agents; D047188:Chalcones; D000666:Amphotericin B; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D011188:Potassium; D004875:Ergosterol