Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana.
Parasitol Res
; 117(1): 45-58, 2018 Jan.
Article
em En
| MEDLINE
| ID: mdl-29159705
ABSTRACT
Leishmaniasis is a neglected tropical disease caused by the parasite of the genus Leishmania. About 13 million people are infected worldwide, and it is estimated that 350 million are at risk of infection. Clinical manifestations depend on the parasite species and factors related to the host such as the immune system, nutrition, housing, and financial resources. Available treatments have severe side effects; therefore, research currently focuses on finding more active and less toxic compounds. Quinoxalines have been described as promising alternatives. In this context, 17 isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated as potential leishmanicidal agents. Their effect on the cell metabolism of Leishmania mexicana promastigotes and their cytotoxic effects on the J774.A1 cell line and on erythrocytes were evaluated, and their selectivity index was calculated. Compounds T-069 (IC50 = 1.49 µg/mL), T-070 (IC50 = 1.71 µg/mL), T-072 (IC50 = 6.62 µg/mL), T-073 (IC50 = 1.25 µg/mL), T-085 (IC50 = 0.74 µg/mL), and T-116 (IC50 = 0.88 µg/mL) were the most active against L. mexicana promastigotes and their mechanism of action was characterized by flow cytometry and microscopy. Compound T-073, the most selective quinoxaline derivative, induced cell membrane damage, phosphatidylserine exposition, reactive oxygen species production, disruption of the mitochondrion membrane potential, and DNA fragmentation, all in a dose-dependent manner, indicating the induction of regulated necrosis. Light and transmission electron microscopy showed the drastic morphological changes induced and the mitochondrion as the most sensitive organelle in response to T-073. This study describes the mechanism by which active isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide quinoxalines affect the parasite.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinoxalinas
/
Leishmania mexicana
/
Antiprotozoários
Limite:
Animals
País/Região como assunto:
Mexico
Idioma:
En
Revista:
Parasitol Res
Assunto da revista:
PARASITOLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
México