A triazole hybrid of neolignans as a potential antileishmanial agent by triggering mitochondrial dysfunction

dc.creatorArruda, Carla Cardozo Pinto de
dc.creatorHardoim, Daiana de Jesus
dc.creatorRizk, Yasmin Silva
dc.creatorSouza, Celeste da Silva Freitas de
dc.creatorValle, Tânia Zaverucha do
dc.creatorCarvalho, Diego Bento
dc.creatorTaniwaki, Noemi Nosomi
dc.creatorBaroni, Adriano Cesar de Morais
dc.creatorCalabrese, Kátia da Silva
dc.date2020-04-23T14:56:55Z
dc.date2020-04-23T14:56:55Z
dc.date2019
dc.date.accessioned2023-09-26T21:16:00Z
dc.date.available2023-09-26T21:16:00Z
dc.identifierARRUDA, 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.
dc.identifier1420-3049
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/40934
dc.identifier10.3390/molecules25010037
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8871760
dc.descriptionIn 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.
dc.formatapplication/pdf
dc.languageeng
dc.publisherMDPI
dc.rightsopen access
dc.subjectLeishmania amazonensis
dc.subjectDerivado sintético
dc.subjectAtividade antileishmanial
dc.subjectMorte celular
dc.subjectUltraestrutura
dc.subjectLeishmania amazonensis
dc.subjectSynthetic derivative
dc.subjectAntileishmanial Activity
dc.subjectCell death
dc.subjectUltrastructure
dc.titleA triazole hybrid of neolignans as a potential antileishmanial agent by triggering mitochondrial dysfunction
dc.typeArticle


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