Analysis of the molecular electrostatic potential for the prediction of N-oxidation and biological activity of substituted pyridines.

Abstract

Comparative studies on the reactivity of the heterocyclic nitrogen were carried out for pyridine and its three monosubstituted derivatives 2-aminopyridine (2-AP), 3-aminopyridine (3-AP), and 4-aminopyridine (4-AP) to reveal the structural basis for the differences in their susceptibility to N-oxidation. Molecular orbital calculations were performed to obtain the wave functions for the calculation of the molecular electrostatic potentials (MEP) generated by the molecules. The comparison of the reactivity of the cyclic nitrogen, evaluated from the depth and accessibility of the minimum in the MEP, indicates that the nitrogen in 4-AP will be most susceptible to protonation and will be the most protected from N-oxidation at physiological pH values. The MEP map for 2-AP reveals the smallest minimum in the series of compounds and a considerable reduction in the accessibility of the region near the cyclic nitrogen caused by the proximal substitution. On this basis, 3-AP becomes the most likely derivative to form the ring N-oxide. Comparison of the conclusions from the MEP analysis with available data from bioassays suggests that the mechanism responsible for the genotoxic effects of the chemicals, where only 3-AP is active, is very different from the mechanism for systemic toxicity where 3-AP is the least active, and 4-AP is most active probably due to its channel blocking properties. As the mechanisms for the biological activities of the N-oxide metabolites become clear, reliable predictions of the toxicity of the pyridines should become possible based on such reactivity characteristics.