In vitro activity and mechanism of action against the protozoan parasite Trypanosoma cruzi of 5-nitrofuryl containing thiosemicarbazones.
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.
Aguirre
Gabriela
G
Departamento de Quimica Orgánica, Facultad de Quimica-Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
Boiani
Lucía
L
Cerecetto
Hugo
H
Fernández
Marcelo
M
González
Mercedes
M
Denicola
Ana
A
Otero
Lucia
L
Gambino
Dinorah
D
Rigol
Carolina
C
Olea-Azar
Claudio
C
Faundez
Mario
M
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
D009581:Nitrofurans; D013882:Thiosemicarbazones