Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles

• Published in: Journal of antimicrobial chemotherapy 2005-12, Vol.56 (6), p.1034-1041
• Main Authors: Menna-Barreto, Rubem F. S., Henriques-Pons, Andrea, Pinto, Antônio V., Morgado-Diaz, José A., Soares, Maurilio J., De Castro, Solange L.
• Format: Article
• Language: English
• Subjects: Acridine Orange - metabolism; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Benzaldehydes - chemistry; Biological and medical sciences; Cells, Cultured; chemotherapy; Chromatin - drug effects; Cytoplasmic Granules - drug effects; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - toxicity; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - parasitology; Medical sciences; Mice; Microscopy, Electron; Mitochondria - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - parasitology; naphthoquinones; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Naphthoquinones - toxicity; Organelles - drug effects; parasites; Pharmacology. Drug treatments; Rhodamine 123 - metabolism; Succinate Cytochrome c Oxidoreductase - antagonists & inhibitors; T. cruzi; Tabebuia; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - isolation & purification; Trypanocidal Agents - pharmacology; Trypanocidal Agents - toxicity; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - growth & development; Trypanosoma cruzi - ultrastructure
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dki403

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.