Author | Arruda, Carla Cardozo Pinto de | |
Author | Hardoim, Daiana de Jesus | |
Author | Rizk, Yasmin Silva | |
Author | Souza, Celeste da Silva Freitas de | |
Author | Valle, Tânia Zaverucha do | |
Author | Carvalho, Diego Bento | |
Author | Taniwaki, Noemi Nosomi | |
Author | Baroni, Adriano Cesar de Morais | |
Author | Calabrese, Kátia da Silva | |
Access date | 2020-04-23T14:56:55Z | |
Available date | 2020-04-23T14:56:55Z | |
Document date | 2019 | |
Citation | ARRUDA, Carla Cardoso Pinto de et al. A triazole hybrid of neolignans as a potential antileishmanial agent by triggering mitochondrial dysfunction. Molecules, v. 25, n. 1, p. 1-13, 20 Dec. 2019. | pt_BR |
ISSN | 1420-3049 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/40934 | |
Language | eng | pt_BR |
Publisher | MDPI | pt_BR |
Rights | open access | |
Subject in Portuguese | Leishmania amazonensis | pt_BR |
Subject in Portuguese | Derivado sintético | pt_BR |
Subject in Portuguese | Atividade antileishmanial | pt_BR |
Subject in Portuguese | Morte celular | pt_BR |
Subject in Portuguese | Ultraestrutura | pt_BR |
Title | A triazole hybrid of neolignans as a potential antileishmanial agent by triggering mitochondrial dysfunction | en_US |
Type | Article | |
DOI | 10.3390/molecules25010037 | pt_BR |
Abstract | In the search for new compounds with antileishmanial activity, we synthesized a triazole hybrid analogue of the neolignans grandisin and machilin G (LASQUIM 25), which was previously found highly active against both promastigotes and intracellular amastigote forms of Leishmania amazonensis. In this work, we investigated the leishmanicidal effects of LASQUIM 25 to identify the mechanisms involved in the cell death of L. amazonensis promastigotes. Transmission electron microscopy (TEM) analysis showed marked effects of LASQUIM 25 (IC50 = 7.2 µM) on the morphology of promastigote forms, notably on mitochondria. The direct action of the triazole derivative on the parasite was noticed over time from 2 h to 48 h, and cells displayed several ultrastructural alterations characteristic of apoptotic cells. Also, flow cytometric analysis (FACS) after TMRE staining detected changes in mitochondrial membrane potential after LASQUIM 25 treatment (64.83% labeling versus 83.38% labeling in nontreated cells). On the other hand, FACS after PI staining in 24 h-treatment showed a slight alteration in the integrity of the cell membrane, a necrotic event (16.76% necrotic cells versus 3.19% staining in live parasites). An abnormal secretion of lipids was observed, suggesting an exocytic activity. Another striking finding was the presence of autophagy-related lysosome-like vacuoles, suggesting an autophagic cell death that may arise as consequence of mitochondrial stress. Taken together, these results suggest that LASQUIM 25 leishmanicidal mechanisms involve some degree of mitochondrial dysregulation, already evidenced by the treatment with the IC50 of this compound. This effect may be due to the presence of a methylenedioxy group originated from machilin G, whose toxicity has been associated with the capacity to generate electrophilic intermediates. | en |
Affilliation | Universidade Federal de Mato Grosso do Sul. Instituto de Biociências. Laboratório de Parasitologia Humana. Campo Grande, MS, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal de Mato Grosso do Sul. Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição. Laboratório de Síntese e Química Medicinal. Campo Grande, MS, Brasil. | pt_BR |
Affilliation | Instituto Adolfo Lutz. Núcleo de Microscopia Eletrônica. São Paulo, SP, Brasil. | pt_BR |
Affilliation | Universidade Federal de Mato Grosso do Sul. Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição. Laboratório de Síntese e Química Medicinal. Campo Grande, MS, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunomodulação e Protozoologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
Subject | Leishmania amazonensis | pt_BR |
Subject | Synthetic derivative | pt_BR |
Subject | Antileishmanial Activity | pt_BR |
Subject | Cell death | pt_BR |
Subject | Ultrastructure | pt_BR |