Repositioning of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts for Chagas disease treatment: Trypanosoma cruzi cell death involving mitochondrial membrane depolarisation and Fe-SOD inhibition

Martín‐Escolano, Rubén; Martín‐Escolano, Javier; Ballesteros‐Garrido, Rafael; Cirauqui, Nuria; Abarca, Belén; Rosales, María J.; Sánchez‐Moreno, Manuel; Ballesteros, Rafaél; Marı́n, Clotilde

doi:10.1007/s00436-020-06779-0

Cited by 7 publications

(4 citation statements)

References 64 publications

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“…This form is responsible for the acute and chronic stages of Chagas disease in mammalian hosts [16]. Epimastigotes were used as a primary screening because their replication is extracellular, and they are easy to handle and maintain in the laboratory [17].…”

Section: Trypanosomicidal Effect Against On the Trypomastigotementioning

confidence: 99%

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

et al. 2021

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In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC 50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.

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Section: Trypanosomicidal Effect Against On the Trypomastigotementioning

confidence: 99%

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

et al. 2021

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“…The SOD activity was, therefore, probably related to the damage caused by the intracellular oxidative state [ 97 ]. Further examples are the two compounds for the leishmanicidal [ 1 , 2 , 3 ]Triazolo[1,5-a]pyridinium salt compound that showed trypanocidal effects through the inhibition of Fe-SOD activity [ 98 ]. Drug susceptibility may, therefore, be strain-dependent [ 94 ].…”

Section: Protistsmentioning

confidence: 99%

Superoxide Dismutases in Eukaryotic Microorganisms: Four Case Studies

Valle

Scheckhuber

2022

Antioxidants

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Various components in the cell are responsible for maintaining physiological levels of reactive oxygen species (ROS). Several different enzymes exist that can convert or degrade ROS; among them are the superoxide dismutases (SODs). If left unchecked, ROS can cause damage that leads to pathology, can contribute to aging, and may, ultimately, cause death. SODs are responsible for converting superoxide anions to hydrogen peroxide by dismutation. Here we review the role of different SODs on the development and pathogenicity of various eukaryotic microorganisms relevant to human health. These include the fungal aging model, Podospora anserina; various members of the genus Aspergillus that can potentially cause aspergillosis; the agents of diseases such as Chagas and sleeping disease, Trypanosoma cruzi and Trypanosoma brucei, respectively; and, finally, pathogenic amoebae, such as Acanthamoeba spp. In these organisms, SODs fulfill essential and often regulatory functions that come into play during processes such as the development, host infection, propagation, and control of gene expression. We explore the contribution of SODs and their related factors in these microorganisms, which have an established role in health and disease.

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“…Finally, organomegaly of spleens and hearts was measured (Figure 6 ). They are manifested in both the acute-and chronic-phases of CD, allow us to characterise the pathogenesis of the T. cruzi Arequipa strain, and also allow us an indirect evaluation of the BNZ efficacy since they are directly associated with the parasitic load (Martín-Escolano et al , 2018, 2020d. Splenomegaly and cardiomegaly occurred in experimentally infected mice in both phases of CD, during which the spleens of infected mice were approximately twice the mass of those from uninfected mice.…”

Section: In Vivo Bnz Resistance Profilementioning

confidence: 99%

Trypanosoma cruzi Arequipa: a tool for Chagas disease drug discovery

Martín‐Escolano

2022

Preprint

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Trypanosoma cruzi, the causative agent of Chagas disease, is a genuine parasite with a tremendous genetic diversity and a complex life cycle. Scientists have studied this disease for more than 100 years, and Chagas disease drug discovery has been a mainstay due to the absence of an effective treatment. Technical advances in several areas have contributed to a better understanding of the complex biology and life cycle of this parasite with the aim of designing the ideal profile of both drug and therapeutic options to treat CD. Here, we present T. cruzi Arequipa strain (MHOM/Pe/2011/Arequipa) as an interesting tool for CD drug discovery. We have characterized acute-phase parasitaemia and chronic-phase tropism in BALB/c mice, and we have determined the in vitro and in vivo benznidazole resistance profile of the different morphological forms of this strain. The tropism of this strain makes it an interesting tool for the screening of new compounds with a potential anti-Chagas profile for the treatment of this disease.

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Repositioning of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts for Chagas disease treatment: Trypanosoma cruzi cell death involving mitochondrial membrane depolarisation and Fe-SOD inhibition

Cited by 7 publications

References 64 publications

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

Superoxide Dismutases in Eukaryotic Microorganisms: Four Case Studies

Trypanosoma cruzi Arequipa: a tool for Chagas disease drug discovery

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