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NOVEL N,N-DI-ALKYLNAPHTHOIMIDAZOLIUM DERIVATIVE OF β-LAPACHONE IMPAIRED TRYPANOSOMA CRUZI MITOCHONDRIAL ELECTRON TRANSPORT SYSTEM
Succinato desidrogenase
Quimioterapia
Naphthoimidazoles
Estresse oxidativo
Succinato desidrogenase
Chemotherapy
Naphthoimidazoles
Mitochondria
Oxidative stress
Succinate dehydrogenase
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Pesquisa em Produtos Naturais. Rio de Janeiro, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Pesquisa em Produtos Naturais. Rio de Janeiro, RJ, Brasil.
Universidade Federal Rural do Rio de Janeiro. Instituto de Química. Seropédica, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Abstract
Trypanosoma cruzi is a protozoan parasite that causes Chagas disease, a neglected tropical disease that is endemic
in Latin America and spreading worldwide due to globalization. The current treatments are based on benzni dazole and nifurtimox; however, these drugs have important limitations and limited efficacy during the chronic
phase, reinforcing the necessity of an alternative chemotherapy. For the last 30 years, our group has been
evaluating the biological activity of naphthoquinones and derivatives on T. cruzi, and of the compounds tested,
N1, N2 and N3 were found to be the most active in vitro. Here, we show the synthesis of a novel β-lapachone derived naphthoimidazolium named N4 and assess its activity on T. cruzi stages and the mechanism of action.
The new compound was very active on all parasite stages (IC50/24 h in the range of 0.8–7.9 μM) and had a
selectivity index of 5.4. Mechanistic analyses reveal that mitochondrial ROS production begins after short
treatment starts and primarily affects the activity of complexes II-III. After 24 h treatment, a partial restoration of
mitochondrial physiology (normal complexes II-III and IV activities and controlled H2O2 release) was observed;
however, an extensive injury in its morphology was still detected. During treatment with N4, we also observed
that trypanothione reductase activity increased in a time-dependent manner and concomitant with increased
oxidative stress. Molecular docking calculations indicated the ubiquinone binding site of succinate dehydroge nase as an important interaction point with N4, as with the FMN binding site of dihydroorotate dehydrogenase.
The results presented here may be a good starting point for the development of alternative treatments for Chagas
disease and for understanding the mechanism of naphthoimidazoles in T. cruzi.
Keywords in Portuguese
Trypanosoma cruziSuccinato desidrogenase
Quimioterapia
Naphthoimidazoles
Estresse oxidativo
Succinato desidrogenase
Keywords
Trypanosoma cruziChemotherapy
Naphthoimidazoles
Mitochondria
Oxidative stress
Succinate dehydrogenase
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