Cargando…

Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lechuga, Guilherme Curty, Borges, Júlio Cesar, Calvet, Claudia Magalhães, de Araújo, Humberto Pinheiro, Zuma, Aline Araujo, do Nascimento, Samara Braga, Motta, Maria Cristina Machado, Bernardino, Alice Maria Rolim, Pereira, Mirian Claudia de Souza, Bourguignon, Saulo Cabral
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971285/
https://www.ncbi.nlm.nih.gov/pubmed/27490082
http://dx.doi.org/10.1016/j.ijpddr.2016.07.001
_version_ 1782446082088763392
author Lechuga, Guilherme Curty
Borges, Júlio Cesar
Calvet, Claudia Magalhães
de Araújo, Humberto Pinheiro
Zuma, Aline Araujo
do Nascimento, Samara Braga
Motta, Maria Cristina Machado
Bernardino, Alice Maria Rolim
Pereira, Mirian Claudia de Souza
Bourguignon, Saulo Cabral
author_facet Lechuga, Guilherme Curty
Borges, Júlio Cesar
Calvet, Claudia Magalhães
de Araújo, Humberto Pinheiro
Zuma, Aline Araujo
do Nascimento, Samara Braga
Motta, Maria Cristina Machado
Bernardino, Alice Maria Rolim
Pereira, Mirian Claudia de Souza
Bourguignon, Saulo Cabral
author_sort Lechuga, Guilherme Curty
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4971285
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-49712852016-08-10 Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi Lechuga, Guilherme Curty Borges, Júlio Cesar Calvet, Claudia Magalhães de Araújo, Humberto Pinheiro Zuma, Aline Araujo do Nascimento, Samara Braga Motta, Maria Cristina Machado Bernardino, Alice Maria Rolim Pereira, Mirian Claudia de Souza Bourguignon, Saulo Cabral Int J Parasitol Drugs Drug Resist Regular Article 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. Elsevier 2016-07-14 /pmc/articles/PMC4971285/ /pubmed/27490082 http://dx.doi.org/10.1016/j.ijpddr.2016.07.001 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular Article
Lechuga, Guilherme Curty
Borges, Júlio Cesar
Calvet, Claudia Magalhães
de Araújo, Humberto Pinheiro
Zuma, Aline Araujo
do Nascimento, Samara Braga
Motta, Maria Cristina Machado
Bernardino, Alice Maria Rolim
Pereira, Mirian Claudia de Souza
Bourguignon, Saulo Cabral
Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title_full Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title_fullStr Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title_full_unstemmed Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title_short Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi
title_sort interactions between 4-aminoquinoline and heme: promising mechanism against trypanosoma cruzi
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971285/
https://www.ncbi.nlm.nih.gov/pubmed/27490082
http://dx.doi.org/10.1016/j.ijpddr.2016.07.001
work_keys_str_mv AT lechugaguilhermecurty interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT borgesjuliocesar interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT calvetclaudiamagalhaes interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT dearaujohumbertopinheiro interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT zumaalinearaujo interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT donascimentosamarabraga interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT mottamariacristinamachado interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT bernardinoalicemariarolim interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT pereiramirianclaudiadesouza interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi
AT bourguignonsaulocabral interactionsbetween4aminoquinolineandhemepromisingmechanismagainsttrypanosomacruzi