Methyl-Hydroxypyridinecarboxylic Acids as Possible Bidentate Chelating Agents for Aluminium(III): Synthesis and Metal Ligand Solution Chemistry

In view of a possible application to aluminium chelation therapy, 1-methyl-3-hydroxy-4-pyridinecarboxylic acid (1M3H4P) and 1-methyl-4-hydroxy-3-pyridinecarboxylic acid (1M4H3P) were synthesized, and their chemical interactions with aluminium(III) were investigated in aqueous 0.6 m (Na)Cl at 25 °C by means of potentiometric titrations. The qualitative and quantitative results obtained were confirmed by UV spectrophotometry and 1H NMR spectroscopy. For both ligands, the species AlL2+, AlL2+, AlL3, and AlL2H-1 were identified, with log?(1,1,0)=7.66, log ?(1,2,0)=14.27, log?(1,3,0)=19.099, and log?(1,2,-1)=7.00 for 1M3H4P, log?(1,1,0)=7.21, log?(1,2,0)=13.41, log?(1,3,0)=18.15, and log?(1,2,-1)=6.4 for 1M4H3P. The chelation strength of 1M3H4P and 1M4H3P is lower than that of other available aluminium( III) chelators, e.g. deferiprone (pAl difference at physiological pH: ca. 3 log units). The octanol/aqueous partitioning values of 1M3H4P and 1M4H3P were 0.0054 and 0.0015, respectively, showing high hydrophilicity. The efficiencies of the ligands to chelate aluminium(III) were evaluated at physiological pH and ion strength "in vitro". 1M3H4P and 1M4H3P were more effective than their non-methylated analogs 3H4P and 4H3P.