Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

Abstract

The synthesis and physicochemical properties of a range of 2- and 6-amido-3-hydroxypyridin-4-ones are described. All the amido-substituted 3-hydroxypyridin-4-ones have lower pK(a) values than 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone). This is due to the inductive effect of the amido group. Furthermore, the pK(a) values of the 3-hydroxy group in 1-nonsubstituted pyridinones are dramatically lower than those of the corresponding 1-alkyl analogues, indicating that a strong hydrogen bond exists between the 2-amido function and the 3-oxygen anion, which stabilises the anion. As a result of the decreased competition with protons, the pFe(3+) values of this group of molecules are higher than that of deferiprone. The distribution coefficients of these molecules are also increased despite the lack of a hydrophobic 1-alkyl substituent and this is ascribed to the intramolecular hydrogen bond. X-ray diffraction studies confirm the existence of the intramolecular hydrogen bond.

Iron Chelating Agents for Iron Overload Diseases

“…On the contrary, when starting from a ligand with pK1 >7.4, an increase of the pFe can be obtained introducing substituents whose inductive and resonance effects lead to a decrease of pK 1 till to 7.4. The effect of pK 1 in determining the pFe value has been also remarked by Piyamangkol et al 27 These authors described a number of 2-and 6-amido-3-hydroxypyridin-4-ones, all characterized by lower pK a values than that of deferiprone, because of the inductive effect of the amido group. Moreover, the pK a values of 1-nonsubstituted pyridinones containing the 3-hydroxy group are dramatically lower than those of the corresponding 1-alkyl analogues.…”

Recent Developments Centered on Orally Active Iron Chelators

“…The lead compound ( Figure 1J) was found to be orally active 74 and highly effective at removing iron from both the iron-loaded rat 74 and marmoset. 75 In similar fashion, Hider and coworkers have demonstrated that the introduction of either a 1-hydroxyalkyl group ( Figure 1K) 76 or an amido function ( Figure 1L) 77 at the 2-position of 3-hydroxypyridin-4-ones enhances the affinity for iron(III) over the pH range 5-8. Although such an effect reduces the overall iron(III) stability constant, it reduces the pKa value of the chelating function by a larger margin.…”

“…Although such an effect reduces the overall iron(III) stability constant, it reduces the pKa value of the chelating function by a larger margin. These combined changes result in an increase in the corresponding pFe 3+ values [75][76][77] due to the reduced competition with hydrogen ions; thus the 2amidopyridin-4-one ( Figure 1L) has a pFe value of 21.7 as compared with that of the analogous deferiprone ( Figure 1H), which possesses a pFe value of 20.5. In practical terms this means that at pH 7.4 ( Figure 1L) binds iron over ten times more tightly than deferiprone.…”

“…77 Detailed dose-response studies suggest that chelators with high pFe 3+ values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridinones and so in principle can be used at lower doses. Several of these compounds are the subject of preclinical evaluation.…”

Chemical features of in use and in progress chelators for iron overload

“…These lower pK a 's led to a decreased proton competition, and therefore to better chelating properties in comparison with those of the parent deferiprone [53]. None of these chelators have been identified with superior efficacy/toxicity ratios than those of DFP [54,55]. As far as the improvement of log P is concerned, an interesting compound, CM 1, was recently proposed (Scheme 4) [56].…”