title: In vitro activity and mechanism of action against the protozoan parasite Trypanosoma cruzi of 5-nitrofuryl containing thiosemicarbazones.
abstract: The in vitro growth inhibition activity of new thiosemicarbazone derivatives against the protozoan parasite Trypanosoma cruzi, the causative agent of American trypanosomiasis, are described. The designed compounds combine in the same molecule the thiosemicarbazone function, recently described as a potent cruzain-inhibitor moiety, and the recognised 5-nitrofuryl group, an oxidative stress promoter. Some of the derivatives were found to be very active against the cultured (epimastigote) form of the parasite, being 1.5-1.7-fold more active than the reference compound, Nifurtimox. Free radicals production was detected when the compounds were incubated in presence of mammalian-liver microsomes. The thiosemicarbazones' capacity to act as pharmacophore in the cruzain inhibition process was theoretically analysed. Frontier molecular orbital HOMO was found as an adequate descriptor in this process. Acute in vivo toxicity of two of the more active derivatives was evaluated. The results showed that these compounds are among the most potent 5-nitrofuryl derivatives tested against this parasite thus support further in vivo studies of some of these thiosemicarbazones.
authors.affiliation: Departamento de Quimica Orgánica, Facultad de Quimica-Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Aguirre
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernández
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Ana
authors.initials: A
authors.lastname: Denicola
authors.forename: Lucia
authors.initials: L
authors.lastname: Otero
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
authors.forename: Carolina
authors.initials: C
authors.lastname: Rigol
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea-Azar
authors.forename: Mario
authors.initials: M
authors.lastname: Faundez
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D009581:Nitrofurans / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D009581:Nitrofurans; D013882:Thiosemicarbazones