Theoretical prediction of relative and absolute pKa values of aminopyridines

This work presents a study aimed at the theoretical prediction of pKa values of aminopyridines, as a factor responsible for the activity of these compounds as blockers of the voltage-dependent K+ channels. To cover a large range of pKa values, a total of seven substituted pyridines is considered as a calibration set: pyridine, 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 2-chloropyridine, 3-chloropyridine, and 4-methylpirydine. Using ab initio G1, G2 and G3 extrapolation methods, and the CPCM variant of the Polarizable Continuum Model for solvation, we calculate gas phase and solvation free energies. pKa values are obtained from these data using a thermodynamic cycle for describing protonation in aqueous and gas phases. The results show that the relatively inexpensive G1 level of theory is the most accurate at predicting pKa values in aminopyridines. The highest standard deviation with respect to the experimental data is 0.69 pKa units for absolute values calculations. The difference increases slightly to 0.74 pKa units when the pKa is computed relative to the pyridine molecule. Considering only compounds at least as basic as pyridine (the values of interest for bioactive aminopyridines) the error falls to 0.10 and 0.12 pKa units for the absolute and relative computations, respectively. The technique can be used to predict the effect of electronegative substituents in the pKa of 4-AP, the most active aminopyridine considered in this work. Thus, 2-chloro and 3-chloro-4-aminopyridine are taken into account. The results show a decrease of the pKa, suggesting that these compounds are less active than 4-AP at blocking the K+ channel.