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The partition coefficients P between n-octanol and water of pyridoxal isonicotinoyl hydrazone and 34 analogues have been determined experimentally; the values indicate that the partition coefficients calculated for these compounds, and previously reported (P. Ponka, D.R. Richardson, J.T. Edward, and F.L. Chubb. Can. J. Physiol. Pharmacol. 72: 659-666. 1994; D.R. Richardson, E.H. Tran, and P. Ponka. Blood, 86: 4294-4306. 1994), are too low by 2-3 orders of magnitude. The calculations, using Rekker's additive method, failed because the molecules have two or more hydrophilic sites close together. More recent additive schemes (CLOGP, KOWWIN, ACD/LogP) also failed. The only reliable method was the semi-empirical method of Hansch. This requires the experimental determination of the partition coefficient of at least one representative in each series of compounds of related structure. In the present paper, determination of log P of three representatives enabled us to calculate the partition coefficients of the other 32 compounds with acceptable accuracy. The new results show that apochelators have maximum activity in releasing 59Fe from reticulocytes when they have log P = 2.8 (P = 630), and not log P = 0 (P = 1), as reported by Ponka et al. (P. Ponka, D.R Richardson, J.T. Edward, and F.L Chubb. Can. J. Physiol. Pharmacol. 72: 659-666 1994).

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.