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

Abstract

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.

• Authors: Guzmán Alvarez, Beatriz Aguirre-López, Nallely Cabrera, Eliã B Marins, Luzineide Tinoco, Carlos Ignacio Batthyány, Marieta Tuena de Gómez-Puyou, Armando Gómez Puyou, Ruy Pérez-Montfort, Hugo Cerecetto, Mercedes González
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 28 Issue 5 Pg. 981-9 (Oct 2013) ISSN: 1475-6374 [Electronic] England
• PMID: 22803666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Thiadiazoles
• Triose-Phosphate Isomerase

Topics

• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship
• Thiadiazoles (chemical synthesis, chemistry, pharmacology)
• Triose-Phosphate Isomerase (antagonists & inhibitors, metabolism)
• Trypanosoma cruzi (drug effects, enzymology, growth & development)