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 Fe³⁺ 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 r² = 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).