Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase

1 3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R 2 substitutents was selected for the investigation of the structure–activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R 2 substitutents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R 2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R 2 segment correlated well with inhibitory activity.