Thermodynamic parameters for the M2+/bifunctional 3-hydroxy-4-pyridinones complex formation at different experimental conditions

This contribution is the result of a speciation study of two bifunctional 3-hydroxy-4-pyridinones (see Figure 1) in aqueous solution and in the presence of biological relevant divalent metal cations, at different temperatures and ionic strengths. The 3-hydroxy-4-pyridinones are a family of compounds developed in view of applications in metal chelation therapy and for the detoxification of human body from hard metal cations (e.g. Al3+, Fe3+). They represent a good alternative to the use of Deferoxamine (DFB),[1] due to their effectiveness at physiological pH range as well as in all the biological conditions, low costs, oral activity and the absence of side effects. These bidentate ligands are derivatives of 1,2-dimethyl-3-hydroxy-4-pyridinone (commercially known as deferiprone, DFP) featuring an aromatoid N-heterocyclic ring and a hydroxyl and a ketone group in ortho position, which confer them a high binding ability toward metal cations such as M2+ and M3+. [3-6] Although this family of metal chelators proved an inherently high affinity towards hardmetal cations, such as Fe3+ and Al3+, it appeared also important to study its interaction with other biological relevant M2+, in order to assure that along with their sequestering role of those hard M3+ there is no significant depletion of important M2+ bio-metal cations. The acid-base properties of the ligands, previously studied at I = 0.15 mol L-1 in NaCl(aq) and T = 298.15 K and 310.15 K,[5] were further investigated by potentiometric and UV-Vis spectrophotometric measurements, carried out at the same I and T = 288.15 K and at 0.50 ≤ I /mol L-1 ≤ 1.00 and T = 298.15 K. Furthermore, their binding ability towards Ca2+, Mg2+, Cu2+, Zn2+ was studied at 0.15 ≤ I / mol L-1 ≤ 1.00 in NaCl(aq) and 288.15 ≤ T / K ≤ 310.15 using the same analytical techniques employed for the acid-base properties investigation. The dependence of the determined protonation and stability constants on ionic strength and temperature was modeled by means of an extended-type Debye-Hückel and the Van’t Hoff equations, respectively. 1H NMR spectroscopic titrations and computational studies were also performed to gain information on the Zn2+-ligands coordination-mode. Finally, the sequestering ability of the 3-hydroxy-4-pyridinones towards M2+ was investigated by the calculation of the empirical parameter pL0.5, already proposed by the research group,[7] at different pH, ionic strength and temperature conditions. It represents the total concentration of ligand required to sequester the 50% of the metal cation present in trace in solution.