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Biological, ultrastructural effect and subcellular localization of aromatic diamidines in Trypanosoma cruzi

Published online by Cambridge University Press:  21 September 2009

D. G. J. BATISTA ,
M. G. O. PACHECO ,
A. KUMAR ,
D. BRANOWSKA ,
M. A. ISMAIL ,
L. HU ,
D. W. BOYKIN  and
M. N. C. SOEIRO
D. G. J. BATISTA
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 962 RJ, Brazil
M. G. O. PACHECO
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 962 RJ, Brazil
A. KUMAR
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, 30302Geogia, USA
D. BRANOWSKA
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, 30302Geogia, USA
M. A. ISMAIL
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, 30302Geogia, USA
L. HU
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, 30302Geogia, USA
D. W. BOYKIN
Affiliation:
Department of Chemistry, Georgia State University, Atlanta, 30302Geogia, USA
M. N. C. SOEIRO*
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, 962 RJ, Brazil
*
*Corresponding author: Laboratory of Cellular Biology, Av. Brasil, 4365, Manguinhos, 962Rio de Janeiro, Brazil. Tel: +055 21 2598 4534. Fax: +055 21 2598 4577. E-mail: soeiro@ioc.fiocruz.br
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Summary

No vaccines or safe chemotherapy are available for Chagas disease. Pentamidine and related di-cations are DNA minor groove-binders with broad-spectrum anti-protozoal activity. Therefore our aim was to evaluate the in vitro efficacy of di-cationic compounds – DB1645, DB1582, DB1651, DB1646, DB1670 and DB1627 – against bloodstream trypomastigotes (BT) and intracellular forms of Trypanosoma cruzi. Cellular targets of these compounds in treated parasites were also analysed by fluorescence and transmission electron microscopy (TEM). DB1645, DB1582 and DB1651 were the most active against BT showing IC50 values ranging between 0·15 and 6·9 μm. All compounds displayed low toxicity towards mammalian cells and DB1645, DB1582 and DB1651 were also the most effective against intracellular parasites, with IC50 values ranging between 7·3 and 13·3 μm. All compounds localized in parasite nuclei and kDNA (with greater intensity in the latter structure), and DB1582 and DB1651 also concentrated in non-DNA-containing cytoplasmic organelles possibly acidocalcisomes. TEM revealed alterations in mitochondria and kinetoplasts, as well as important disorganization of microtubules. Our data provide further information regarding the activity of this class of compounds upon T. cruzi which should aid future design and synthesis of agents that could be used for Chagas disease therapy.

Keywords

Trypanosoma cruziChagas diseasechemotherapyaromatic diamidines
Type
Research Article
Information
Parasitology , Volume 137 , Issue 2 , February 2010 , pp. 251 - 259
Copyright
Copyright © Cambridge University Press 2009

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