Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment.
Chagas' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC(50)s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas' disease treatment.
Batista
Denise da Gama Jaén
Dda G
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Batista
Marcos Meuser
MM
de Oliveira
Gabriel Melo
GM
do Amaral
Patrícia Borges
PB
Lannes-Vieira
Joseli
J
Britto
Constança Carvalho
CC
Junqueira
Angela
A
Lima
Marli Maria
MM
Romanha
Alvaro José
AJ
Sales Junior
Policarpo Ademar
PA
Stephens
Chad E
CE
Boykin
David W
DW
Soeiro
Maria de Nazaré Correia
Mde N
D000578:Amidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D004562:Electrocardiography; D005260:Female; D005663:Furans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure
C552046:2,5-bis(2-(2-propoxy)-4-(2-pyridylimino)aminophenyl)furan; D000578:Amidines; D005663:Furans; D014344:Trypanocidal Agents
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