Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets

OTERO, LUCÍA; M. VIEITES; A. DENICOLA; C. RIGOL; L. OPAZO; C. OLEA- AZAR; J. D. MAYA; A. MORELLO; R. L. KRAUTH-SIEGEL; OSCAR ENRIQUE PIRO

Journal of Medicinal Chemistry

Año: 2006 vol. 49 p. 3322 - 3331

0022-2623

In the search for new therapeutic tools against American Trypanosomiasis palladium complexes with bioactive nitrofuran-containing thiosemicarbazones as ligands were obtained. Sixteen novel palladium (II) complexes with the formulas [PdCl2(HL)] and [Pd(L)2] were synthesized, and the crystal structure of [Pd(5-nitrofuryl-3-acroleine thiosemicarbazone)2].3DMSO was solved by X-ray diffraction methods. Most complexes showed higher in vitro growth inhibition activity against Trypanosoma cruzi than the standard drug Nifurtimox. In most cases, the activity of the ligand was maintained or even increased as a result of palladium complexation. In addition, the complexes’ mode of antitrypanosomal action was investigated. Although the complexes showed strong DNA binding, all data strongly suggest that the main trypanocidal mechanism of action is the production of oxidative stress as a result of their bioreduction and extensive redox cycling. Moreover, the complexes were found to be irreversible inhibitors of trypanothione reductase.