Unveiling the antioxidant potential of newly designed phenylethylamine derivatives through computational chemistry: Significance of acid dissociation constants

We have calculated the pKa and the primary antioxidant capacity of the six possible designed isomers of phenylethylamine substituted with a catechol and a carboxylic group. The reaction of these phenylethylamine designed derivatives (Phdd) with a hydroperoxyl radical (center dot OOH) was studied in both lipid and aqueous environments. The Gaussian 09 computer program was used within the Density Functional Theory, with the M05-2X functional, the 6-311 + G(d,p) basis set, and the SMD continuous solvent model, to perform the necessary thermodynamic and kinetic calculations. The entire study includes the determination of the Phdd pKa values, their center dot OOH reaction mechanisms, as well as the relative importance of the protonated and deprotonated forms of Phdd at physiological pH in aqueous solution. Compounds Ph178, Ph179 and Ph182 are found to be excellent primary antioxidants against center dot OOH in water at physiological pH. In lipid medium Ph178 and Ph182, could inhibit the damage caused by the hydroperoxyl radical.