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


CONCLUSIONS
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.
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República , Uruguay.
Guzmán
G
Alvarez
Beatriz
B
Aguirre-López
Nallely
N
Cabrera
Eliã B
EB
Marins
Luzineide
L
Tinoco
Carlos Ignacio
CI
Batthyány
Marieta Tuena
MT
de Gómez-Puyou
Armando Gómez
AG
Puyou
Ruy
R
Pérez-Montfort
Hugo
H
Cerecetto
Mercedes
M
González
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development
D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D014305:Triose-Phosphate Isomerase