Trypanosoma cruzi: activity of heterocyclic cationic molecules in vitro.
Chagas disease remains a serious public health problem in several Latin American countries. New chemotherapy is urgently needed since current drugs are limited in efficacy and exhibit undesirable side effects. Aromatic diamidines and analogs are well known anti-parasitic agents and in this study, we have evaluated the in vitro trypanocidal effect of several different heterocyclic cationic compounds, including diamidines (DB1195, DB1196 and DB1345), a monoamidine (DB824), an arylimidamide (DB613A) and a guanylhydrazone (DB1080) against amastigotes and bloodstream trypomastigotes of Trypanosoma cruzi, the etiological agent of Chagas disease. Our present findings showed that all compounds exerted, at low-micromolar doses, a trypanocidal effect upon both intracellular parasites and bloodstream trypomastigotes of T. cruzi. The activity of DB1195, DB1345, DB824 and DB1080 against bloodstream forms was reduced when these compounds were assayed in the presence of mouse blood possibly due to their association with plasma constituents and/or due to metabolic instability of the compounds. However, trypanocidal effects of DB613A and DB1196 were not affected by plasma constituents, suggesting their potential application in the prophylaxis of banked blood. In addition, potency and selectivity of DB613A, towards intracellular parasites, corroborate previous results that demonstrated the highly promising activity of arylimidamides against this parasite, which justify further studies in experimental models of T. cruzi infection.
Pacheco
Michele Gabriele de Oliveira
MG
Lab. Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, M.N.C. Soeiro, Rio de Janeiro, Brazil.
da Silva
Cristiane França
CF
de Souza
Elen Mello
EM
Batista
Marcos Meuser
MM
da Silva
Patrícia Bernardino
PB
Kumar
Arvind
A
Stephens
Chad E
CE
Boykin
David W
DW
Soeiro
Maria de Nazaré C
Mde N
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
D000578:Amidines; D006571:Heterocyclic Compounds; D014344:Trypanocidal Agents