The increasing interest in medicinal chemistry and drug discovery vividly illustrates how far is modern society from fast, reliable, and efficient drug discovery, which must rely on precisely established synthesis–structure–activity relationships. This poses inorganic chemists the challenging task of designing suitable metal-based drugs with predictable and desirable biological activities, which can be reasonably correlated to interactions with predefined biomolecular targets. In this context coordination complexes of vanadium are of great interest in the last 30 years due to their promising antidiabetic activity.

The antidiabetic potential of vanadium compounds is well documented and a wide range of compounds, including simple salts and its coordination complexes, had been tested for insulin-mimicking activity in streptozotocin-induced diabetic Wistar rats [[1], [2], [3], [4]]. Several compounds, including VOSO4 [5] and [VO(etylmaltolato)2] [6] have completed phase I and phase II of clinical trials. Although the exact mechanism by which metal ions and complexes act as insulin mimics is still unknown, it seems that redox processes must be critical elements for the biological activity of vanadium compounds, since vanadium complexes differing only in oxidation state have diverse biological features [7]. Indeed, there is evidence that insulin receptors are activated by inhibiting protein tyrosine phosphatase (PTP1B), which is connected to the activation of cytosolic nonreceptor tyrosine kinase, direct phosphorylation of insulin receptor substrate 1 (IRS1) and activation of phosphatidylinositol 3 kinase (PI3 (PDE)) [8,9].

From the structural point of view VIVO moiety is important in designing new insulin-mimicking agents since most of the complexes showing good antidiabetic activity contain this structural feature [10]. Moreover, it seems that regardless on oxidation state of vanadium complex administered in vivo VIVO specie is likely the form transported in blood as the most stable form in reducing biological environments [11]. On the other hand, hydrazones are versatile class of stereochemically flexible organic ligands which ligate metals mostly as bidentate or tridentate neutral, monoanionic or dianionic ligands in keto-amine or enol-imine form [12]. Additionally, diverse possibilities of controlling the donor atoms of hydrazone ligands provide synthetic routes to complexes with attractive structural, magnetic, electrochemical, catalytic or biological properties in which structure – activity relationships can be meaningfully established [13].

Given that the activity, distribution, metabolism and excretion of drugs is significantly affected by binding to albumin as the most abundant plasma protein, investigation of the interaction of new compounds with albumin is one of the first steps in the biological evaluation of new compounds [14]. It was empirically established that large binding constant of drugs with proteins leads to strong, most often irreversible binding, which sometimes results in drugs being inactivated before reaching their molecular target [[15], [16], [17], [18]]. Certainly, the exceptions are compounds whose intentional binding to a protein increases their bioactivity. In this contest, preparing the vanadium complexes having a moderate affinity toward albumin, would give good drug candidates.

Here, we report the synthesis and full characterization of five novel heteroleptic oxidovanadium(IV) complexes of salicylaldehyde-based 2-furoic acid hydrazones, along with the promising in vivo antidiabetic activity of nitro derivative. Furthermore, the mild hypoalbuminemia observed in vivo motivated the study of complex – albumin interaction in vitro to gather the insight into the nature of binding.