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

Molecules

Marcos Couto³  Carina Sánchez³  Belén Dávila³  Valentina Machín³  Javier Varela³  Guzmán Álvarez³  Mauricio Cabrera³  Laura Celano²  Beatriz Aguirre-López¹  Nallely Cabrera¹  Marieta Tuena de Gómez-Puyou¹  Armando Gómez-Puyou¹  Ruy Pérez-Montfort¹  Hugo Cerecetto³  Mercedes González³ 

[1] Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; E-Mails:;Laboratorio de Enzimología, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo C.P. 11400, Uruguay; E-Mail:;Grupo de Química Medicinal-Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo C.P. 11400, Uruguay; E-Mails:

关键词: anti-T. cruzi activity;    3H-1;    2-dithiole;    triosephosphate isomerase;    cruzipain;    membrane sterol biosynthesis;    ¹H-NMR metabolomics;   

DOI  :  10.3390/molecules200814595

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.