Synthesis, Physicochemical Characterization, and Biological Evaluation of 2-(1‘-Hydroxyalkyl)-3-hydroxypyridin-4-ones: Novel Iron Chelators with Enhanced pFe3+ Values

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Abstract
The synthesis of a range of 2-(1‘-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pKa values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1‘-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe3+ values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1‘-hydroxyethyl)-3-hydroxypyridin-4-one (pFe3+ = 21.4) and 1,6-dimethyl-2-(1‘-hydroxyethyl)-3-hydroxypyridin-4-one (pFe3+ = 21.5) where an enhancement on pFe3+ values in the region of two orders of magnitude is observed, as compared with Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) (pFe3+ = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [59Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe3+ values show great promise in their ability to remove iron under in vivo conditions.