Theoretical Prediction of the Phenoxyl Radical Formation Capacity and Cyclooxygenase Inhibition Relationships by Phenolic Compounds

Abstract

AbstractDue to the importance of the O‐H bond dissociation in the antioxidant mechanism of anti‐inflammatory phenols, we studied the biradical process Ph‐OH→PhO.+H. for 25 phenolic compounds using ab initio calculations. Enthalpies of reaction (ΔHr), changes in the electron density at the O‐H bond critical point (ρOH) and total atomic charges of ortho and para carbon atoms strongly correlate with the in vitro inhibition of cyclooxygenase activity by phenols. The most active compounds have large values of the electron density at the O‐H bond (ρOH), thus favouring the O‐H bond dissociation. In contrast, inactive compounds have small values of the electron density at the O‐H bond (ρOH), thus reducing the hydrogen donation ability. These results are also supported by the representation of the molecular electrostatic potentials maps. The prediction of the cyclooxygenase inhibitory activity of the proposed QSAR equations is analysed using the multilineal (MLR) method. Finally, the differences in biological activity are examined by analysing the binding interactions of active compounds in the pocket site of human COX‐2 enzyme structure derived from crystallographic X ‐ray data.