Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Relationship of the lipophilicity of the apochelator to its ability to mobilise iron from reticulocytes in vitro

Abstract

Analogues of the iron (III) chelator, pyridoxal isonicotinoyl hydrazone (PIH) show high potential as orally active agents for the treatment of iron-overload diseases, such as thalassemia. In the present study, the n-octanol–water partition coefficients of 30 analogues of PIH were measured by thin-layer chromatography and also calculated using the additive schemes of Rekker. The purpose was to examine the relationship between lipophilicity of the apochelator and its ability to promote the release of 59Fe from reticulocytes loaded with nonheme 59Fe. Interestingly, maximum activity occurred when the partition coefficient of the apochelator was approximately 1 (log P = 0). Considering the results in the context of the design and synthesis of more active analogues of PIH, it can be suggested that before initiating synthesis, a useful indication of biological activity can be determined by examining the lipophilicity of the molecule, using the schemes of Rekker to calculate the partition coefficient. By using this strategy, analogues of PIH with inappropriate lipophilicity can be excluded before initiating the expensive process of screening in biological models.Key words: iron chelation, iron mobilisation, iron overload, pyridoxal isonicotinoyl hydrazone.