Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/16534
Title: Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
Authors: Lechuga, Guilherme Curty
Borges, Júlio Cesar
Calvet, Claudia Magalhães
Araújo, Humberto Pinheiro de
Zuma, Aline Araujo
Nascimento, Samara Braga do
Motta, Maria Cristina Machado
Bernardino, Alice Maria Rolim
Pereira, Mirian Claudia de Souza
Bourguignon, Saulo Cabral
Affilliation: Universidade Federal Fluminense. Departamento de Biologia Celular e Molecular. a Laboratório de Interação Celular e Molecular. Niterói, RJ, Brasil.
Universidade Federal Fluminense. Departamento de Química Organica. Niterói, RJ, Brasil / Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro. Nilópolis, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Controle de Qualidade em Saúde. Departamento de Imunologia. Rio de Janeiro, RJ. Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Departamento de Biologia Celular e Molecular. a Laboratório de Interação Celular e Molecular. Niterói, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil.
Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro. Nilópolis, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ. Brasil.
Universidade Federal Fluminense. Departamento de Biologia Celular e Molecular. a Laboratório de Interação Celular e Molecular. Niterói, RJ, Brasil.
Abstract: Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 μM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 μM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies.
Keywords: Quinoline
Heme
Trypanosoma cruzi
Chemotherapy
Chagas Disease
keywords: Doença de Chagas
Quimioterapia
Trypanosoma cruzi
Heme
Quinolina
Issue Date: 2016
Publisher: Elsevier
Citation: LECHUGA, Guilherme Curty; et al. Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi. International Journal for Parasitology: Drugs and Drug Resistance, v.6, p.154-164, 2016.
DOI: 10.1016/j.ijpddr.2016.07.001
ISSN: 2211-3207
Copyright: open access
Appears in Collections:INCQS - Artigos de Periódicos
IOC - Artigos de Periódicos

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