Potent in vitro anti-Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal complexes having an inhibitory effect on parasite-specific fumarate reductase

  • Marisol Vieites
  • Pablo Smircich
  • Beatriz Parajón-Costa
  • Jorge Rodríguez
  • Verónica Galaz
  • Claudio Olea-Azar
  • Lucía Otero
  • Gabriela Aguirre
  • Hugo Cerecetto
  • Mercedes González
  • Alicia Gómez-Barrio
  • Beatriz Garat
  • Dinorah Gambino
Original Paper
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Accepted:

Abstract

In the search for new therapeutic tools against Chagas disease (American trypanosomiasis) palladium and platinum complexes of the bioactive ligand pyridine-2-thiol N-oxide were exhaustively characterized and evaluated in vitro. Both complexes showed high in vitro growth inhibition activity (IC50 values in the nanomolar range) against Trypanosoma cruzi, the causative agent of the disease. They were 39–115 times more active than the antitrypanosomal drug Nifurtimox. The palladium complex showed an approximately threefold enhancement of the activity compared with the parent compound. In addition, owing to their low unspecific cytotoxicity on mammalian cells, the complexes showed a highly selective antiparasite activity. To get an insight into the mechanism of action of these compounds, DNA, redox metabolism (intraparasite free-radical production) and two parasite-specific enzymes absent in the host, namely, trypanothione reductase and NADH-fumarate reductase, were evaluated as potential parasite targets. Additionally, the effect of metal coordination on the free radical scavenger capacity previously reported for the free ligand was studied. All the data strongly suggest that trypanocidal action of the complexes could mainly rely on the inhibition of the parasite-specific enzyme NADH-fumarate reductase.

Keywords

Pyridine-2-thiol N-oxide Palladium Platinum NADH fumarate reductase Chagas disease 
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Notes

Acknowledgments

This work was partially supported by PEDECIBA of Uruguay, TWAS Research Grant 05-312 RG/CHE/LA and Prosul-CNPq project 490209/2005-0. B.P-C. is member of the Research Career of CONICET. We wish to thank R. Luise Krauth-Siegel, Heidelberg University, Germany, for performing the TR inhibition studies and O.E. Piro, Universidad Nacional de La Plata, Argentina, for performing helpful crystal parameter measurements of single crystals of the complexes.

Supplementary material

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Copyright information

© SBIC 2008

Authors and Affiliations

  • Marisol Vieites
    • 1
  • Pablo Smircich
    • 2
  • Beatriz Parajón-Costa
    • 3
  • Jorge Rodríguez
    • 4
  • Verónica Galaz
    • 4
  • Claudio Olea-Azar
    • 4
  • Lucía Otero
    • 1
  • Gabriela Aguirre
    • 5
  • Hugo Cerecetto
    • 5
  • Mercedes González
    • 5
  • Alicia Gómez-Barrio
    • 6
  • Beatriz Garat
    • 2
  • Dinorah Gambino
    • 1
  1. 1.Cátedra de Química Inorgánica, Facultad de QuímicaUniversidad de la RepúblicaMontevideoUruguay
  2. 2.Laboratorio de Interacciones Moleculares, Facultad de CienciasUniversidad de la RepúblicaMontevideoUruguay
  3. 3.Centro de Química Inorgánica (CEQUINOR/CONICET-UNLP), C.C. 962, Facultad de Ciencias ExactasUniversidad Nacional de La PlataLa PlataArgentina
  4. 4.Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y FarmacéuticasUniversidad de ChileSantiagoChile
  5. 5.Laboratorio de Química Orgánica, Facultad de Química–Facultad de CienciasUniversidad de la RepúblicaMontevideoUruguay
  6. 6.Departamento de Parasitología, Facultad de FarmaciaUniversidad ComplutenseMadridSpain

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