Synthesis and characterizations of pyridazine-based iron chelators

Abstract

In an attempt to design ligands which require both a high iron(III) affinity and a low iron(II) affinity, the 3-hydroxypyridin-4-one structure has been modified to introduce an additional nitrogen atom in the pyridine ring to form a pyridazine. The target molecules were synthesized from a chlorine-substituted pyridazine using step-by-step methoxylations. A total of six 3- and 5-hydroxypyridazin-4(1H)-ones have been synthesized, with a methyl, ethyl or n-propyl group on the N1 of the pyridazine ring. In the reaction of the pyridazines with alkyl iodide, the presence of acetone drives the reaction to afford pyridazinones rather than the desired pyridaziniums. The pK_a values of the free ligands, the stability constants of their iron(III) complexes and corresponding pFe^III values demonstrate that this type of ligand has lower values when compared with those of deferiprone. The reduction potential values of the iron complexes obtained from cyclic voltammetry measurements, are used to determine the corresponding pFe^II values. Although two compounds of the 20 series have marginally higher log β₃(Fe^III)/log β₃(Fe^II) ratios than those of deferiprone, they possess pFe^III values <20, indicating that this type of chelator is unlikely to be optimized into a useful therapeutic agent.