1,2,4-thiadiazol-5(4 H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition.

Autor: Alvarez, Guzmán, Aguirre-López, Beatriz, Cabrera, Nallely, Marins, Eliã B., Tinoco, Luzineide, Batthyány, Carlos Ignacio, de Gómez-Puyou, Marieta Tuena, Puyou, Armando Gómez, Pérez-Montfort, Ruy, Cerecetto, Hugo, González, Mercedes
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Zdroj: Journal of Enzyme Inhibition & Medicinal Chemistry; Oct2013, Vol. 28 Issue 5, p981-989, 9p
Abstrakt: 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(4 H)-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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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