Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi : is oxidative stress involved?

Dublin Core

Título

Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi : is oxidative stress involved?

Tema

TRIPANOSOMIASIS
ENFERMEDAD DE CHAGAS
NIFURTIMOX
TRIPANOSOMA CRUZI
ESTRES OXIDATIVO
BIBLIOGRAFIA NACIONAL QUIMICA
2010

Abstract

Chagas disease is caused by the trypanosomatid parasite Trypanosoma cruzi and threatens millions of lives in South America. As other neglected diseases there is almost no research and development effort by the pharmaceutical industry and the treatment relies on two drugs, Nifurtimox and Benznidazole, discovered empirically more than three decades ago. Nifurtimox, a nitrofurane derivative, is believed to exert its biological activity through the bioreduction of the nitro-group to a nitro-anion radical which undergoes redox-cycling with molecular oxygen. This hypothesis is generally accepted, although arguments against it have been presented. In the present work we studied the ability of Nifurtimox and five N-oxide-containing heterocycles to induce oxidative stress in T. cruzi. N-Oxide-containing heterocycles represent a promising group of new trypanosomicidal agents and their mode of action is not completely elucidated. The results here obtained argue against the oxidative stress hypothesis almost for all the studied compounds, including Nifurtimox. A significant reduction in the level of parasitic low-molecular-weight thiols was observed after Nifurtimox treatment; however, it was not linked to the production of reactive oxidant species. Besides, redox-cycling is only observed at high Nifurtimox concentrations (>400 mM), two orders ofmagnitude higher than the concentration required for anti-proliferative activity (5 mM). Our results indicate that an increase in oxidative stress is not the main mechanism of action of Nifurtimox. Among the studied N-oxide-containing heterocycles, benzofuroxan derivatives strongly inhibited parasite dehydrogenase activity and affected mitochondrial membrane potential. The indazole derivative raised intracellular oxidants production, but it was the least effective as anti-T. cruzi.

Autor

Boiani Santurio, Mariana
Piacenza, Lucía
Hernández, Paola
Boiani Santurio, Lucía
Cerecetto, Hugo
González, Mercedes
Denicola Creci, Ana Beatriz

Fuente

Biochemical Pharmacology v. 79, no. 12, 2010. -- p.1736 - 1745

Editor

Elsevier

Fecha

2010

Derechos

Información sobre Derechos de Autor

(Por favor lea este aviso antes de abrir los documentos u objetos)

La legislación uruguaya protege el derecho de autor sobre toda creación literaria, científica o artística, tanto en lo que tiene que ver con sus derechos morales, como en lo referente a los derechos patrimoniales con sujeción a lo establecido por el derecho común y las siguientes leyes

(LEY 9.739 DE 17 DE DICIEMBRE DE 1937 SOBRE PROPIEDAD LITERARIA Y ARTISTICA CON LAS MODIFICACIONES INTRODUCIDAS POR LA LEY DE DERECHO DE AUTOR Y DERECHOS CONEXOS No. 17.616 DE 10 DE ENERO DE 2003, LEY 17.805 DE 26 DE AGOSTO DE 2004, LEY 18.046 DE 24 DE OCTUBRE DE 2006 LEY 18.046 DE 24 DE OCTUBRE DE 2006)

ADVERTENCIA - La consulta de este documento queda condicionada a la aceptación de las siguientes condiciones de uso: Este documento es únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con fines de lucro. Esta reserva de derechos afecta tanto los datos del documento como a sus contenidos. En la utilización o cita de partes debe indicarse el nombre de la persona autora.

Formato

PDF

Idioma

Inglés

Tipo

Artículo

Identificador

doi:10.1016/j.bcp.2010.02.009

Document Item Type Metadata

Original Format

PDF
Fecha de agregación
November 28, 2014
Colección
Bibliografía Nacional Química
Tipo de Elemento
Document
Etiquetas
, , , ,
Citación
Boiani Santurio, Mariana, “Mode of action of Nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi : is oxidative stress involved?,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed July 17, 2019, http://riquim.fq.edu.uy/items/show/2098.
Archivos