Computational Investigation of the Antioxidant Activity of Dihydroxybenzoic Acids in Aqueous and Lipid Media

Abstract

Reactive free radicals have both beneficial and destructive effects. Indeed, at physiological levels, free radicals help to preserve homeostasis by acting as signal transducers. However, excessive generation of free radicals can harm and damage membranes, proteins, and DNA, among other cell structures. Dihydroxybenzoic acids (DHBAs) have proven their antioxidant capacity against a large variety of free radicals, as well as their ability to inhibit or restrict reactive species overproduction. In this paper, a computational analysis of the antioxidant activity of a series of DHBAs in polar and nonpolar media was carried out at the DFT/M06-2X/6-[Formula: see text] level of theory. The implicit SMD solvation model was used in order to rationalize the experimental findings and to investigate the solvent effect on the mechanism and the radical scavenging ability. The obtained results put in evidence that HAT is the predominant mechanism in nonpolar media, whereas SPLET is more favored in polar environment. The BDE[Formula: see text], [Formula: see text], and [Formula: see text] descriptors are used to predict the most reactive hydroxyl groups and the antioxidant activity order of the studied DHBAs. Our results are in total agreement with experimental findings (inhibition of lipid peroxidation and scavenging of hydrogen peroxide). Moreover, this study shows that the substitution of the hydrogen atom by strong electron-donating groups, namely NMe2, in the ortho positions of the best experimental DHBAs leads to a significant enhancement of their antioxidant activity.