Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment

Denise Da Gama Jaén Batista, Marcos Meuser Batista, Gabriel Melo De Oliveira, Patrícia Borges Do Amaral, Joseli Lannes-Vieira, Constança Carvalho Britto, Angela Junqueira, Marli Maria Lima, Alvaro José Romanha, Policarpo Ademar Sales, Chad E. Stephens, David W. Boykin, Maria De Nazaré Correia Soeiro

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Abstract

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 IC50s (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.

Original languageEnglish (US)
Pages (from-to)2940-2952
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number7
DOIs
StatePublished - Jul 1 2010

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Batista, D. D. G. J., Batista, M. M., De Oliveira, G. M., Do Amaral, P. B., Lannes-Vieira, J., Britto, C. C., Junqueira, A., Lima, M. M., Romanha, A. J., Sales, P. A., Stephens, C. E., Boykin, D. W., & Soeiro, M. D. N. C. (2010). Arylimidamide DB766, a potential chemotherapeutic candidate for Chagas' disease treatment. Antimicrobial Agents and Chemotherapy, 54(7), 2940-2952. https://doi.org/10.1128/AAC.01617-09