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Alvarez, Guzman; Aguirre-Lopez, Beatriz; Cabrera, Nallely; Marins, Elia B; Tinoco, Luzineide; Ignacio Batthyany, Carlos; Tuena de Gomez-Puyou, Marieta; Gomez Puyou, Armando; Perez-Montfort, Ruy; Cerecetto, Hugo; Gonzalez, Mercedes (2013)

1,2,4-THIADIAZOL-5(4H)-ONES: A NEW CLASS OF SELECTIVE INHIBITORS OF TRYPANOSOMA CRUZI TRIOSEPHOSPHATE ISOMERASE. STUDY OF THE MECHANISM OF INHIBITION

J Enzyme Inhib Med Chem 28(5):981-989
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Context: Triosephosphate isomerase (TIM) is a ubiquitous enzyme that has been targeted for the discovery of small molecular weight compounds with potential use against Trypanosoma cruzi, the causative agent of Chagas disease. We have identified a new selective inhibitor chemotype of TIM from T. cruzi (TcTIM), 1,2,4-thiadiazol-5(4H)-one. Objective: Study the mechanism of TcTIM inhibition by a 1,2,4-thiadiazol derivative. Methods: We performed the biochemical characterization of the interaction of the 1,2,4-thiadiazol derivative with the wild-type and mutant TcTIMs, using DOSY-NMR and MS experiments. Studies of T. cruzi growth inhibition were additionally carried out. Results and conclusion: At low micromolar concentrations, the compound induces highly selective irreversible inactivation of TcTIM through non-covalent binding. Our studies indicate that it interferes with the association of the two monomers of the dimeric enzyme. We also show that it inhibits T. cruzi growth in culture.