title: Selective inactivation of triosephosphate isomerase from Trypanosoma cruzi by brevifolin carboxylate derivatives isolated from Geranium bellum Rose.
abstract: In the search of molecules that can serve as leads in the design of a new drug for the treatment of Chagas' disease, we found that some brevifolin carboxylate derivatives isolated from Geranium bellum Rose, inactivate triosephosphate isomerase from Trypanosoma cruzi (TcTIM) in a species-specific manner. After spectroscopic characterization, these compounds were identified as methylbrevifolin carboxylate (1), ethylbrevifolin carboxylate (2), butylbrevifolin carboxylate (3) and the methylated derivate methyl tri-O-methylbrevifolin carboxylate (4). The concentrations required to inactivate fifty percent the activity of TcTIM were 6.5, 8 and 14 microM of 1, 2 and 3, respectively, while compound 4 had no inhibitory effect. Molecular docking simulations of 1 on the structure of TcTIM showed that residues of both monomers interact with the compound. These compounds are very selective with respect to the parasite enzyme, since they showed no effect on the activity of human TIM at concentrations as high as 1mM. In conclusion, the brevifolin carboxylate derivatives described here are excellent leads in the search of a new chemotherapy for the treatment of this disease.
authors.affiliation: Area Académica de Farmacia, Universidad Autónoma del Estado de Hidalgo, Exhacienda La Concepción, Tilcuautla, Hidalgo 42160, Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Gayosso-De-Lucio
authors.forename: Martin
authors.initials: M
authors.lastname: Torres-Valencia
authors.forename: Arturo
authors.initials: A
authors.lastname: Rojo-Domínguez
authors.forename: Hugo
authors.initials: H
authors.lastname: Nájera-Peña
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aguirre-López
authors.forename: José
authors.initials: J
authors.lastname: Salas-Pacheco
authors.forename: Claudia
authors.initials: C
authors.lastname: Avitia-Domínguez
authors.forename: Alfredo
authors.initials: A
authors.lastname: Téllez-Valencia
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001665:Binding Sites; D014355:Chagas Disease / Q000188:drug therapy; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D031315:Geranium / Q000737:chemistry*; D006801:Humans; D043823:Taxoids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D014305:Triose-Phosphate Isomerase / Q000737:chemistry / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: C523498:8,9-single-epoxy brevifolin; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D043823:Taxoids; D014305:Triose-Phosphate Isomerase