Journal Article

Effect of a β-lapachone-derived naphthoimidazole on <i>Trypanosoma cruzi</i>: identification of target organelles

Rubem F. S. Menna-Barreto, Andrea Henriques-Pons, Antônio V. Pinto, José A. Morgado-Diaz, Maurilio J. Soares and Solange L. De Castro

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 56, issue 6, pages 1034-1041
Published in print December 2005 | ISSN: 0305-7453
Published online November 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dki403
Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles

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Objectives: Investigation of the mode of action of the naphthoimidazole N1, obtained from the reaction of β-lapachone with benzaldehyde, which among 45 semi-synthetic derivatives of naphthoquinones isolated from Tabebuia sp. was one of the most active compounds against Trypanosoma cruzi trypomastigotes.

Methods: Quantification of the effect of N1 against the proliferative forms of T. cruzi, and investigation of potential targets in the parasite using electron microscopy and flow cytometry techniques.

Results: N1 presented the following order of activity: amastigotes > trypomastigotes > epimastigotes. The effect on intracellular forms was ∼25 times higher than on macrophages and heart muscle cells. N1-treated parasites presented an abnormal chromatin condensation and mitochondrial damage. In epimastigotes, alterations of reservosomes were observed, and in trypomastigotes, a decrease in the electron density of acidocalcisomes was observed. In epimastigotes, the naphthoimidazole inhibited the activity of succinate cytochrome c reductase. Labelling with rhodamine 123 or Acridine Orange was decreased in both forms treated with N1.

Conclusions: The results suggest that epimastigotes, reservosomes, mitochondrion, and nucleus contain N1 targets. In trypomastigotes, in which reservosomes are absent, the organelles affected by the compound were also the mitochondrion and nucleus, as well as acidocalcisomes, in which the decrease in electron density could be due to the use of polyphosphate as an alternative energy supply.

Keywords: T. cruzi; chemotherapy; naphthoquinones; parasites

Journal Article.  3932 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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