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Molecules 2015, 20(8), 14595-14610; doi:10.3390/molecules200814595

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

1
Grupo de Química Medicinal-Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo C.P. 11400, Uruguay
2
Laboratorio de Enzimología, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo C.P. 11400, Uruguay
3
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
Current address: Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Ruta 3 (km 363), Paysandú C.P. 60000, Uruguay.
Current address: Área de Radiofarmacia, Centro de Investigaciones Nucleares, Universidad de la República, Mataojo 2055, Montevideo C.P. 11400, Uruguay.
*
Authors to whom correspondence should be addressed.
Academic Editor: Christophe Dardonville
Received: 29 May 2015 / Accepted: 7 August 2015 / Published: 12 August 2015
(This article belongs to the Special Issue Antiparasitic Agents)
View Full-Text   |   Download PDF [1011 KB, uploaded 12 August 2015]   |  

Abstract

The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease. View Full-Text
Keywords: anti-T. cruzi activity; 3H-1,2-dithiole; triosephosphate isomerase; cruzipain; membrane sterol biosynthesis; 1H-NMR metabolomics anti-T. cruzi activity; 3H-1,2-dithiole; triosephosphate isomerase; cruzipain; membrane sterol biosynthesis; 1H-NMR metabolomics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Couto, M.; Sánchez, C.; Dávila, B.; Machín, V.; Varela, J.; Álvarez, G.; Cabrera, M.; Celano, L.; Aguirre-López, B.; Cabrera, N.; de Gómez-Puyou, M.T.; Gómez-Puyou, A.; Pérez-Montfort, R.; Cerecetto, H.; González, M. 3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies. Molecules 2015, 20, 14595-14610.

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