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JAC Advance Access originally published online on August 11, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):747-750; doi:10.1093/jac/dkp290
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

In vitro analyses of the effect of aromatic diamidines upon Trypanosoma cruzi

Anissa Daliry1, Patrícia B. Da Silva1, Cristiane F. Da Silva1, Marcos Meuser Batista1, Solange L. De Castro1, Richard R. Tidwell2 and Maria de Nazaré C. Soeiro1,*

1 Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil 2 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Received 7 May 2009; returned 19 June 2009; revised 29 June 2009; accepted 19 July 2009

* Corresponding author. Tel: +55-21-2598-4534; Fax: +55-21-2598-4577; E-mail: soeiro{at}ioc.fiocruz.br

Objectives: Aromatic diamidines (ADs) have been recognized as promising antiparasitic agents. Therefore, in the present work, the in vitro trypanocidal effect of 11 ADs upon the relevant clinical forms of Trypanosoma cruzi was evaluated, as well as determining their toxicity to mammalian cells and their subcellular localization.

Methods: The trypanocidal effect upon trypomastigotes and amastigotes was evaluated by light microscopy through the determination of the IC50 values. The cytotoxicity was determined by the MTT colorimetric assay against mouse cardiomyocytes. For the subcellular localization, transmission electron microscopy and fluorescence approaches were used. The fluorescence intensity within the kinetoplast DNA (kDNA) and nuclear DNA (nDNA) of treated parasites was determined using the Image J program.

Results: Compounds 2, 5 and 7 showed the lowest IC50 values (micromolar range) against intracellular amastigotes and trypomastigotes. In the presence of blood, all the tested ADs exhibited a reduction of their activity. The compounds did not exhibit toxicity to cardiac cells and the highest selectivity index (SI) was achieved by compound 5 with an SI of >137 for trypomastigotes and compound 7 with an SI of >107 for intracellular parasites. The subcellular effects upon bloodstream forms treated with compounds 5 and 7 were mainly on kDNA, leading to its disorganization. The higher accumulation in the kDNA observed for all tested ADs was not directly related to their efficacy.

Conclusions: Our results show the high activity of this new series of ADs against both trypomastigote and amastigote forms, with excellent SIs, especially compound 7, which merits further in vivo evaluation.

Keywords: chemotherapy , Chagas disease , kDNA , intracellular localization


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