A Computational Study of the Reactions between Dehydrozingerone Derivatives and the Hydroperoxyl Radical in Aqueous and Lipid Media

Abstract

Dehydrozingerone (the half-analogue of curcumin) is a natural product that is isolated from ginger rhizomes. Recent studies have shown that this compound displays several physiological activities including antioxidant properties, and it can scavenge oxygen-free radicals like hydroxyl, peroxyl and superoxide radicals. In this work, the thermodynamic and kinetic aspects of the antiradical activity of the natural dehydrozingerone DHZ0 (R=H) and the designed derivatives DHZ1 (R=CHO), DHZ2 (R=OMe) and DHZ3 (R=NMe2) towards the hydroperoxyl radical (HOO•) were investigated at the M06-2X/6-311[Formula: see text]G([Formula: see text],[Formula: see text]) level of theory. The calculations have been performed in gas phase, pentyl ethanoate and water solvents using the implicit SMD solvation model. Four potential mechanisms have been investigated, namely, hydrogen atom transfer (HAT), single-electron transfer followed by proton transfer (SET-PT), sequential proton loss electron transfer (SPLET) and radical adduct formation (RAF). The obtained results show that the SET-PT and RAF mechanisms are endergonic processes and are thermodynamically disfavored, whereas the exergonic HAT process is predicted as the most thermodynamically favored mechanism in all media. The SPLET mechanism was excluded due the minor proportions of the anion species at physiological pH. Kinetic calculations show that DHZ3 reacts with HOO• 1860, 1250 and 215 times faster than DHZ0 in gas phase, pentyl ethanoate, and water, respectively. Based on thermodynamic and kinetic calculations, the designed compound DHZ3 is predicted as a good candidate for hydroperoxyl scavenging in both polar and nonpolar media. Drug likeness evaluation of the studied DHZ derivatives shows that the pharmacokinetic parameters satisfy all the Lipinski and Veber rules.