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

Abstract

Trypanosomatidae is a family of unicellular parasites belonging to the phylum Euglenozoa, which are causative agents in high impact human diseases such as Leishmaniasis, Chagas disease and African sleeping sickness. The impact on human health and local economies, together with a lack of satisfactory chemotherapeutic treatments and effective vaccines, justifies stringent research efforts to search for new disease therapies. Here, we present in vitro trypanocidal activity data and mode of action data, repositioning leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts against Trypanosoma cruzi, the aetiological agent of Chagas disease. This disease is one of the most neglected tropical diseases and is a major public health issue in Central and South America. The disease affects approximately 6–7 million people and is widespread due to increased migratory movements. We screened a suite of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salt compounds, of which compounds 13, 20 and 21 were identified as trypanocidal drugs. These compounds caused cell death in a mitochondrion-dependent manner through a bioenergetic collapse. Moreover, compounds 13 and 20 showed a remarkable inhibition of iron superoxide dismutase activity of T. cruzi, a key enzyme in the protection from the damage produced by oxidative stress.

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Funding

This work was financially supported by the Ministerio de Economia, Industria y Competitividad (CONSOLIDER CSD2010–00065 and CTQ2017–90852-REDC), including funds from the European Regional Development Fundings (ERDF), Generalitat Valenciana Prometeo 2015/002 and from University of Valencia (Spain) (UV-INV-AE 15-332846). RM-E received an FPU Grant [FPU14/01537] from the Ministry of Education of Spain. Central Services for Experimental Research (SCSIE, Universitat de València) and U26 of ICTS NANBIOSIS platform provided the equipment employed.

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RM-E and CM designed the study. RM-E, JM-E, RB-G and NC performed the experiments. RM-E, JM-E and NC collected and analysed the data. RM-E, RB-G and NC wrote the manuscript. RM-E, RB-G, BA, MJR, MS-M, RB and CM reviewed and edited the manuscript. All the authors discussed the results and contributed to the final manuscript.

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Correspondence to Clotilde Marín.

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Martín-Escolano, R., Martín-Escolano, J., Ballesteros-Garrido, R. et al. 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. Parasitol Res (2020). https://doi.org/10.1007/s00436-020-06779-0

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Keywords

  • Chagas disease
  • Chemotherapy
  • Pyridines
  • Superoxide dismutase
  • Trypanocidal agents
  • Trypanosoma cruzi