Novel N,N-di-alkylnaphthoimidazolium derivative of β-lapachone impaired Trypanosoma cruzi mitochondrial electron transport system

Bombaça, Ana Cristina S.; Silva, Leonardo A.; Chaves, Otávio Augusto; Silva, Lorrainy S. da; Barbosa, Juliana M. C.; Silva, Ari M. da; Ferreira, Aurélio B. B.; Menna-Barreto, Rubem F.S.

doi:10.1016/j.biopha.2020.111186

Cited by 9 publications

(9 citation statements)

References 54 publications

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“…The activity of N4 involves elevated ROS production and decreased activity of complex II-III in the first hours of treatment (2 and 4 h); apart from the morphological and functional impairment of this organelle in longer times (24 h). (33) In 2009, our group also evidenced the effect of naphthofuranquinones in the mitochondrial metabolism of T. cruzi stages. These compounds exhibited powerful effects on the protozoa mitochondrion, which appeared drastically swollen and with a washed-out matrix phenotype, in addition to significant reduction of complex I-III activity and succinate-induced O 2 consumption.…”

Section: Potential Drug Targets In Trypanosomatid Mitochondrion and O...mentioning

confidence: 86%

“…(26,27) It has been extensively described that chemical characteristics can confer high redox potential to some classes of drugs, resulting in ROS production during the treatment. (6,28,29,30,31,32,33) The first mechanistic studies evaluating the effects of quinones in trypanosomatids were performed in the late 1970's. In T. cruzi, epimastigotes treated with β-lapachone had increased mitochondrial ROS production, which was inhibited by the addition of the antioxidant enzyme superoxide dismutase.…”

Section: Potential Drug Targets In Trypanosomatid Mitochondrion and O...mentioning

confidence: 99%

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Is the mitochondrion a promising drug target in trypanosomatids?

Pedra-Rezende

Bombaça

Menna-Barreto

2022

Mem. Inst. Oswaldo Cruz

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The trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are etiological agents of important neglected tropical diseases, affecting millions of people worldwide, and the drugs available for these diseases present several limitations. Novel efficient and nontoxic drugs are necessary as an alternative to the current chemotherapy. The unique mitochondrion of trypanosomatids and its peculiar features turn this organelle a potential drug target. Several phenotypic studies describe the damage in the parasite mitochondrial ultrastructure, but the molecular target is unknown. Few reports demonstrated the electron transport system (ETS) as a target due to the high similarities to mammalian orthologues, hence ETS is not a good candidate for drug intervention. On the other hand, antioxidant enzymes, such as trypanothione reductase, and an alternative oxidase (AOX) seem to be interesting targets; however no high active inhibitors were developed up to now. Finally, due to the remarkable differences to mammalian machinery, together with the high biological importance for the parasite survival, the mitochondrial import system stands out as a very promising target in trypanosomatids. Archaic translocase of the outer membrane (ATOM) and translocase of the inner membrane (TIM) complexes, which mediate both protein and tRNA import, composed by specific subunits of these parasites, could be excellent candidates, deserving studies focused on the development of specific drugs.

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Section: Potential Drug Targets In Trypanosomatid Mitochondrion and O...mentioning

confidence: 86%

Section: Potential Drug Targets In Trypanosomatid Mitochondrion and O...mentioning

confidence: 99%

Is the mitochondrion a promising drug target in trypanosomatids?

Pedra-Rezende

Bombaça

Menna-Barreto

2022

Mem. Inst. Oswaldo Cruz

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“…Interestingly, in these studies the increased ROS production was associated with mitochondrial damage, evidenced by the organelle swelling and reduction in the mitochondrial membrane potential. More recently, our group demonstrated the crucial role of mitochondrial ROS generation for the trypanocidal activity of naphthoimidazoles derived from beta-lapachone isolated from Tabebuia trees [ 43 , 44 ]. These previous data pointed to a close relation between mitochondrial injury (primary or not) and the increase of ROS generation.…”

Section: Discussionmentioning

confidence: 99%

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

et al. 2023

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Phytomonas serpens is a trypanosomatid phytoparasite, found in a great variety of species, including tomato plants. It is a significant problem for agriculture, causing high economic loss. In order to reduce the vegetal infections, different strategies have been used. The biological activity of molecules obtained from natural sources has been widely investigated to treat trypanosomatids infections. Among these compounds, chalcones have been shown to have anti-parasitic and anti-inflammatory effects, being described as having a remarkable activity on trypanosomatids, especially in Leishmania species. Here, we evaluated the antiprotozoal activity of the chalcone derivative (NaF) on P. serpens promastigotes, while also assessing its mechanism of action. The results showed that treatment with the derivative NaF for 24 h promotes an important reduction in the parasite proliferation (IC50/24 h = 23.6 ± 4.6 µM). At IC50/24 h concentration, the compound induced an increase in reactive oxygen species (ROS) production and a shortening of the unique flagellum of the parasites. Electron microscopy evaluation reinforced the flagellar phenotype in treated promastigotes, and a dilated flagellar pocket was frequently observed. The treatment also promoted a prominent autophagic phenotype. An increased number of autophagosomes were detected, presenting different levels of cargo degradation, endoplasmic reticulum profiles surrounding different cellular structures, and the presence of concentric membranar structures inside the mitochondrion. Chalcone derivatives may present an opportunity to develop a treatment for the P. serpens infection, as they are easy to synthesize and are low in cost. In order to develop a new product, further studies are still necessary.

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“…One of the most frequent morphological features of autophagy identified in these parasites is the presence of concentric membrane structures or myelin-like structures. Ultrastructural studies noted this structure in protozoa treated with all classes of compounds ( Vannier-Santos et al, 1995 ; Benchimol, 1999 ; Braga et al, 2005 ; Granthon et al, 2006 ; Uzcátegui et al, 2007 ; Menna-Barreto et al, 2009a , b ; Carvalho et al, 2010 ; Bombaça et al, 2018 , 2021 ; Martínez-García et al, 2018 ; Araujo-Silva et al, 2021 ).…”

Section: Autophagic Phenotypes In Drug-treated Parasitesmentioning

confidence: 93%

Different Drugs, Same End: Ultrastructural Hallmarks of Autophagy in Pathogenic Protozoa

et al. 2022

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Protozoan parasites interact with a wide variety of organisms ranging from bacteria to humans, representing one of the most common causes of parasitic diseases and an important public health problem affecting hundreds of millions of people worldwide. The current treatment for these parasitic diseases remains unsatisfactory and, in some cases, very limited. Treatment limitations together with the increased resistance of the pathogens represent a challenge for the improvement of the patient’s quality of life. The continuous search for alternative preclinical drugs is mandatory, but the mechanisms of action of several of these compounds have not been described. Electron microscopy is a powerful tool for the identification of drug targets in almost all cellular models. Interestingly, ultrastructural analysis showed that several classes of antiparasitic compounds induced similar autophagic phenotypes in trypanosomatids, trichomonadids, and apicomplexan parasites as well as in Giardia intestinalis and Entamoeba spp. with the presence of an increased number of autophagosomes as well as remarkable endoplasmic reticulum profiles surrounding different organelles. Autophagy is a physiological process of eukaryotes that maintains homeostasis by the self-digestion of nonfunctional organelles and/or macromolecules, limiting redundant and damaged cellular components. Here, we focus on protozoan autophagy to subvert drug effects, discussing its importance for successful chemotherapy.

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Novel N,N-di-alkylnaphthoimidazolium derivative of β-lapachone impaired Trypanosoma cruzi mitochondrial electron transport system

Cited by 9 publications

References 54 publications

Is the mitochondrion a promising drug target in trypanosomatids?

Is the mitochondrion a promising drug target in trypanosomatids?

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro

Different Drugs, Same End: Ultrastructural Hallmarks of Autophagy in Pathogenic Protozoa

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