title: Massive screening yields novel and selective Trypanosoma cruzi triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity.
abstract: 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.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Montevideo, Uruguay.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Alvarez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aguirre-López
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
authors.forename: Gloria V
authors.initials: GV
authors.lastname: López
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Williams
authors.initials: W
authors.lastname: Porcal
authors.forename: Rossanna
authors.initials: R
authors.lastname: Di Maio
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Nallely
authors.initials: N
authors.lastname: Cabrera
authors.forename: Ruy
authors.initials: R
authors.lastname: Pérez-Montfort
authors.forename: Marieta Tuena
authors.initials: MT
authors.lastname: de Gómez-Puyou
authors.forename: Armando
authors.initials: A
authors.lastname: Gómez-Puyou
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D014305:Triose-Phosphate Isomerase