New oxidovanadium(IV) N-acylhydrazone complexes: Promising antileishmanial and antitrypanosomal agents

Searching for new promising metal-based hits against Dypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [(VO)-O-IV(LASSBio1064-2H)(H2O)], 1, and [(VO)-O-IV(LASSBio1064-2H)(phen)]center dot(H2O), 2, where LASSBio1064 = (E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and V-51 NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)]center dot(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 +/- 0.6 mu M. The compounds show low toxicity on mammalian cells (IC50 > 100 mu M). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [(VO)-O-IV(LASSBio1064-2H)(phen)]center dot(H2O) may be a promising compound for further drug development stages. (C) 2012 Elsevier Masson SAS. All rights reserved.