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Antimicrobial Agents and Chemotherapy, September 2008, p. 3307-3314, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00038-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi{triangledown} ,{dagger}

Cristiane França da Silva,1 Marcos Meuser Batista,1 Denise da Gama Jaen Batista,1 Elen Mello de Souza,1 Patrícia Bernardino da Silva,1 Gabriel Melo de Oliveira,1 Andrea Souza Meuser,1 Abdur-Rafay Shareef,2 David W. Boykin,2 and Maria de Nazaré C. Soeiro1*

Lab. Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil,1 Department of Chemistry, Georgia State University, Atlanta, Georgia2

Received 9 January 2008/ Returned for modification 22 February 2008/ Accepted 24 June 2008

Aromatic diamidines are DNA minor groove-binding ligands that display excellent antimicrobial activity against fungi, bacteria, and protozoa. Due to the currently unsatisfactory chemotherapy for Chagas’ disease and in view of our previous reports regarding the effect of diamidines and analogues against both in vitro and in vivo Trypanosoma cruzi infection, this study evaluated the effects of a diarylthiophene diamidine (DB1362) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas’ disease. The data show the potent in vitro activity of DB1362 against both parasite forms that are relevant for mammalian infection at doses which do not exhibit cytotoxicity. Ultrastructural analysis and flow cytometry studies show striking alterations in the nuclei and mitochondria of the bloodstream parasites. In vivo studies were performed at two different drug concentrations (25 and 50 mg/kg/day) using a 2-day or a 10-day regimen. The best results were obtained when acutely infected mice were treated with two doses at the lower concentration, resulting in 100% survival, compared to the infected and untreated mice. Although it did not display higher efficacy than benznidazole, DB1362 reduced both cardiac parasitism and inflammation, and in addition, it protected against the cardiac alterations (determined by measurements) common in T. cruzi infection. These results support further investigation of diamidines and related compounds as potential agents against Chagas’ disease.

* Corresponding author. Mailing address: Lab. Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil 4365, Manguinhos, 21045-900, Rio de Janeiro, RJ, Brazil. Phone: (55-21) 25984534. Fax: (55-21) 25984577. E-mail: soeiro{at}ioc.fiocruz.br

{triangledown} Published ahead of print on 14 July 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3307-3314, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00038-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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