N-Arylamine derivatives of 3-hydroxy-4-pyridinones: solution studies and bioevaluation in view of Al-detoxification roles

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo–hydrophilic balance of the compounds, and ⁶⁷Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid–base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (pAl1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo–hydrophilic character (–0.2D_oct./water<+1.1). The effect of each ligand on the biodistribution of ⁶⁷Ga in overloaded mice is rapid blood clearance for all of them, but with different biodistribution patterns, namely excretion pathways and brain uptake/clearance, thus suggesting potential different clinical use.