In silico design of hydrazone antioxidants and analysis of their free radical-scavenging mechanism by thermodynamic studies

Abstract

Antioxidants are very crucial in maintaining the normal function of body cells, as they scavenge excess free radical in the body. A set of hydrazone antioxidants was designed by in silico screening. The density functional theory (DFT) method was employed to explore the reaction energetics of their free radical-scavenging mechanism. With the aid of the developed quantitative structure-activity relationship (QSAR) model for hydrazone antioxidants, the structure and antioxidant activity of these compounds were predicted. Three potential reaction mechanisms were investigated, namely, hydrogen atom transfer (HAT), single-electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). Bond dissociation enthalpy (BDE), adiabatic ionization potential (AIP), proton dissociation enthalpy (PDE), proton affinity (PA), electron transfer enthalpy (ETE) and Gibbs free energy that characterize the various steps in these mechanisms were calculated in the gas phase. A total of 25 hydrazone antioxidants were designed, in which the molecule MHD 017 gave the best antioxidant activity. Among the tested molecules, MHD 017 at the 10-OH site gave the best results for the various thermodynamic parameters calculated. The reaction Gibbs free energy results also indicate that this is the most favoured site for free radical scavenge. The obtained results show that HAT and SPLET mechanisms are the thermodynamically plausible reaction pathways of free radical scavenge by hydrazone antioxidants. The reactivity of these compounds towards the hydroperoxyl radical (HOO·) was greater than that towards the methyl peroxyl radical (CH3OO·) based on the exergonicity of the calculated reaction Gibbs free energy.