Prediction of 3-hydroxypyridin-4-one (HPO) hydroxyl pKa values

Abstract

As an aid in optimising the design of 3-hydroxypyridin-4-ones (HPOs) intended for use as therapeutic Fe(3+) chelating agents, various quantum mechanical (QM) and semi-empirical (QSAR) methods have been explored for predicting the pK(a) values of the hydroxyl groups in these compounds. Using a training set of 15 HPOs with known hydroxyl pK(a) values, reliable predictions are shown to be obtained with QM calculations using the B3LYP/6-31+G(d)/CPCM model chemistry (with Pauling radii, and water as solvent). With this methodology, the observed hydroxyl pK(a) values for the training set compound are closely matched by the predicted pK(a) values, with the correlation between the observed and predicted values giving r(2) = 0.98. Predictions subsequently made by this method for a test set of 48 HPOs of known hydroxyl pK(a) values (11 of which were determined experimentally in this study), gave predicted pK(a) values accurate to within ±0.2 log units. In order to further investigate the predictive power of the method, two novel HPOs were synthesised and their hydroxyl pK(a) values were determined experimentally. Comparison of these predicted pK(a) values against the measured values gave absolute deviations of 0.13 (10.18 vs. 10.31) and 0.43 (5.58 vs. 5.15).