Trypanocidal activity of 2-propen-1-amine derivatives on trypomastigotes culture and in animal model.
The cis and trans isomers (either E or Z isomers) of the unsubstituted and bromo-2-propen-1-amine derivatives were evaluated in vitro on Trypanosoma cruzi. The results showed that cis is the most active isomeric form against trypomastigote forms of T. cruzi, indicating that it may contribute most to the trypanocidal effect. All mice which received 5 mg kg(-1) daily for 9 consecutive days, or 200 mg kg(-1) in a single dose of the bromo derivative of 2-propen-1-amine, survived after an infection with 10(4) trypomastigotes/ml of the Y-strain of T. cruzi. They also had a significantly lower parasitemia than the controls. However, with 100 mg kg(-1) of benznidazol for 9 consecutive days, 25% of the animals died by the end of the evaluation 40 days after infection. The involvement of the biosynthesis of ergosterol in the trypanocidal effect of the unsubstituted 2-propen-1-amine derivative was investigated on proliferative epimastigote forms of the parasite. The chromatographic analyses of the lipid extracts obtained from parasites treated with 2-propen-1-amine derivatives and controls (not treated) revealed that growth inhibition is correlated with the accumulation of squalene and the decrease of ergosterol levels. These results suggest that inhibition of the biosynthesis of ergosterol is an important target for the action of the 2-propen-1-amine derivative on T. cruzi through the inhibition of the enzyme squalene epoxidase.
Oliveira
D A
DA
Instituto de Química, Biological Chemistry Laboratory, Universidade Estadual de Campinas, Campinas, CP 6154, CEP 13083-970, São Paulo, S.P., Brazil.
Pereira
D G
DG
Fernandes
A M A P
AM
De Castro
S L
SL
Souza Brito
A R M
AR
De Souza
A O
AO
Durán
N
N
D000588:Amines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D003470:Culture Media; D006801:Humans; D008297:Male; D051379:Mice; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics
D000588:Amines; D003470:Culture Media; D014344:Trypanocidal Agents