Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity.
Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), an enzyme in the glycolytic pathway that exhibits high catalytic rates of glyceraldehyde-3-phosphate- and dihydroxyacetone-phosphate-isomerization only in its dimeric form, was screened against an in-house chemical library containing nearly 230 compounds belonging to different chemotypes. After secondary screening, twenty-six compounds from eight different chemotypes were identified as screening positives. Four compounds displayed selectivity for TcTIM over TIM from Homo sapiens and, concomitantly, in vitro activity against T. cruzi.
Alvarez
Guzmán
G
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Aguirre-López
Beatriz
B
Varela
Javier
J
Cabrera
Mauricio
M
Merlino
Alicia
A
López
Gloria V
GV
Lavaggi
María Laura
ML
Porcal
Williams
W
Di Maio
Rossanna
R
González
Mercedes
M
Cerecetto
Hugo
H
Cabrera
Nallely
N
Pérez-Montfort
Ruy
R
de Gómez-Puyou
Marieta Tuena
MT
Gómez-Puyou
Armando
A
D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D014305:Triose-Phosphate Isomerase