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Antimicrobial Agents and Chemotherapy, October 2009, p. 4414-4421, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00104-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Experimental Chemotherapy against Trypanosoma cruzi Infection Using Ruthenium Nitric Oxide Donors {triangledown}

Jean Jerley N. Silva,1 Wander R. Pavanelli,2 José Clayston M. Pereira,1 João S. Silva,2 and Douglas W. Franco1*

Departamento de Química e Física Molecular, Instituto de Química de São Carlos—Universidade de São Paulo, São Carlos, SP, Brazil,1 Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil2

Received 23 January 2009/ Returned for modification 19 April 2009/ Accepted 25 June 2009

The ruthenium NO donors of the group trans-[Ru(NO)(NH3)4L]n+, where the ligand (L) is N-heterocyclic H2O, SO32–, or triethyl phosphite, are able to lyse Trypanosoma cruzi in vitro and in vivo. Using half-maximal (50%) inhibitory concentrations against bloodstream trypomastigotes (IC50try) and cytotoxicity data on mammalian V-79 cells (IC50V79), the in vitro therapeutic indices (TIs) (IC50V79/IC50try) for these compounds were calculated. Compounds that exhibited an in vitro TI of ≥10 and trypanocidal activity against both epimastigotes and trypomastigotes with an IC50try/epi of ≤100 µM were assayed in a mouse model for acute Chagas' disease, using two different routes (intraperitoneal and oral) for drug administration. A dose-effect relationship was observed, and from that, the ideal dose of 400 nmol/kg of body weight for both trans-[Ru(NO)(NH3)4isn](BF4)3 (isn, isonicotinamide) and trans-[Ru(NO)(NH3)4imN](BF4)3 (imN, imidazole) and median (50%) effective doses (ED50) of 86 and 190 nmol/kg, respectively, were then calculated. Since the 50% lethal doses (LD50) for both compounds are higher than 125 µmol/kg, the in vivo TIs (LD50/ED50) of the compounds are 1,453 for trans-[Ru(NO)(NH3)4isn](BF4)3 and 658 for trans-[Ru(NO)(NH3)4imN](BF4)3. Although these compounds exhibit a marked trypanocidal activity and are able to react with cysteine, they exhibit very low activity in T. cruzi-glycosomal glyceraldehyde-3-phosphate dehydrogenase tests, suggesting that this enzyme is not their target. The trans-[Ru(NO)(NH3)4isn](BF4)3 and trans-[Ru(NO)(NH3)4imN](BF4)3 compounds are able to eliminate amastigote nests in myocardium tissue at 400-nmol/kg doses and ensure the survival of all infected mice, thus opening a novel set of therapies to try against trypanosomatids.

* Corresponding author. Mailing address: Departamento de Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São Paulo (USP), Av. Trabalhador Sãocarlense, 400, CP 780 São Carlos, SP, Brazil. Phone and fax: 55 16 3373 9976. E-mail: douglas{at}iqsc.usp.br

{triangledown} Published ahead of print on 6 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4414-4421, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00104-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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