Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana

Karla Fabiola Chacón-Vargas, Sergio Andrade-Ochoa, Benjamín Nogueda-Torres, Dulce Carolina Juárez-Ramírez, Edgar E. Lara-Ramírez, Ricardo Mondragón-Flores, Antonio Monge, Gildardo Rivera, Luvia Enid Sánchez-Torres

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)45-58
Number of pages14
JournalParasitology Research
Volume117
Issue number1
DOIs
StatePublished - 1 Jan 2018

Keywords

  • Cell death
  • Leishmaniasis
  • Mechanism of action
  • Quinoxaline 1,4-di-N-oxide

Fingerprint

Dive into the research topics of 'Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana'. Together they form a unique fingerprint.

Cite this