A new series of heteroleptic oxidovanadium(iv) compounds with phenanthroline-derived co-ligands: selective Trypanosoma cruzi growth inhibitors

Abstract

Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(IV) complexes, [V(IV)O(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative (L1-L5) and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial-equatorial mode. The stability of the complexes in solution was investigated by EPR and (51)V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [V(IV)O(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure-activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by (1)H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the complexes display an ability to interact with this biomolecule.

Preface: Celebrating vanadium science with leading bioinorganic contributions from the 9th International Vanadium Symposium

“…The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox. Several of the complexes are more active than previously reported for complexes of other NN co-ligands [10]. Whereas all the complexes interact well with DNA with binding modes and strength tuned in by the NN and semicarbazone co-ligands, molecular docking suggests the observed anti-T. cruzi activity cannot be explained by citing DNA intercalation as the sole mechanism of action.…”

Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity

“…Semicarbazone ligands L1-L7 ( Fig. 1) were synthesized from an equimolar mixture of the corresponding aldehyde and semicarbazide and characterized by C, H and N elemental analyses, and FTIR spectroscopy [31][32][33][34][35][36].…”

“…In addition, a metabolomic study carried out by incubating the parasite with the two most active V IV O-compounds pointed the mitochondrion and/or related enzymatic systems as potential targets for these complexes. In addition, coordination to vanadium may improve bioavailability due to increased lipophilicity of the phenanthroline derivatives upon coordination [32].…”

“…Moreover, the highly electrophilic epoxyphen may react with protein nucleophiles and DNA through the epoxide-moiety, while the nucleophilic aminophen may react/interact with biological electrophiles through the amino moiety. The QSAR study led to a design guide for the development of new compounds, with improved biological profiles [31,32].…”

“…In respect to the mechanism of action of the compounds, their interaction with DNA was assessed through different techniques: agarose gel electrophoresis, viscosity measurements and atomic force microscopy (AFM) [18,[26][27][28][29][30][31][32]. In addition, a metabolomic study carried out by incubating the parasite with the two most active V IV O-compounds pointed the mitochondrion and/or related enzymatic systems as potential targets for these complexes.…”