Design, synthesis and evaluation of novel 2-substituted 3-hydroxypyridin-4-ones: Structure-activity investigation of metalloenzyme inhibition by iron chelators

A range of novel 3-hydroxypyridin-4-ones with different R-2 substitutents has been synthesized for the investigation of the structure-activity relationship between the chemical nature of the ligand and the inhibitory activity of the iron-containing metalloenzyme 5-lipoxygenase. Results indicate that the molecular dimensions, together with the lipophilicity, have a critical impact on the ability of this class of chelator to inhibit 5-lipoxygenase. Hydrophilic ligands with a bulky R-2 substitutent tend to be weak inhibitors; thus 1,6-dimethyl-2-(4'-N-n-propylsuccinamido)methyl-3-hydroxypyridin-4(1H)-o ne (22b) which has the largest R-2 substitutent only caused 2% inhibition of the enzyme activity after 30 min incubation at 110 muM IBE (iron-binding equivalents), as compared with deferiprone which caused 40% inhibition of the enzyme activity, under the same conditions.