Bifunctional 3-hydroxy-4-pyridinones as effective aluminium chelators: synthesis, solution equilibrium studies and in vivo evaluation

Abstract

This paper reports the results on the study of a set of synthesized bifunctional 3-hydroxy-4-pyridinones chelators as potential aluminium sequestering agents. They were N-functionalized with alkyl-amino, -carboxylic and -(amino-carboxylic) groups, envisaging the improvement of the Al³⁺ sequestering capacity, in comparison with the marketed chelating drug deferiprone. The main focus of this work was given to the assessment of their binding ability towards Al³⁺, which was studied by potentiometric and UV-Vis spectrophotometric measurements carried out at T = 298.15 K. The speciation models were characterized by Al_pL_qH_r^(3p+r-qz) species with different stoichiometry. Depending on ligand side-chain structures and on their thermodynamic properties, different trends of stability was found. Furthermore, the sequestering ability of the ligands towards Al³⁺ was investigated by the calculation of pL_0.5 values at different experimental conditions. These results clearly indicate that the presence of amino-carboxylic groups in the ligands increases the sequestering ability towards Al³⁺. The in silico evaluation of pharmacokinetic descriptors indicated no violation to the Lipinski's rule and drug-likeness properties. Furthermore, the in vivo bioassays on a model of metal-overload mice showed for three investigated ligands a higher metal-sequestering capacity than for the chelating drug deferiprone, thus suggesting their potential interest as Al-chelating drug candidates.

Keywords: 3-Hydroxy-4-pyridinones; Al(3+) complexation; In vivo chelation; Protonation; Sequestering ability; Speciation.