Computational Investigation of the Antioxidant Activity of Sesamol and its ortho Amino Derivatives in polar and nonpolar environments: Quantum chemical, Molecular Docking and Druglikeness studies

Abstract

The natural sesamol, present in the seeds and oil of sesame, has attracted considerable interest for its powerful antioxidant properties. Its ability to neutralize free radicals and to inhibit lipid peroxidation highlight its potential as a therapeutic agent to reduce the oxidative stress. This explains the beneficial effects of sesamol as effective protectors against the damaging effects of reactive oxygen species (ROS). The antioxidant activity of sesamol and its ortho mono- and di-substituted amino (R= NH₂, NHMe and NHCN) derivatives was investigated at the SMD//M06-2X/6-311+G(d,p) computational level. The calculations were performed in the gas phase and in non-polar (toluene) and polar (ethanol and water) solvents. The main mechanisms, namely, HAT, SPLET and SET-PT were thoroughly investigated and analyzed. The obtained results put in evidence that HAT and SPLET are the thermodynamically favored mechanisms in non-polar and polar media respectively, while SET-PT was found a disfavored mechanism in all media. The obtained results also show that di-substitution with strong electron-donating groups in the ortho position leads to significant increase in their antioxidant activity compared to the reference molecule (sesamol). The antioxidant activity of the sesamol derivatives was also evaluated by molecular docking to explore the possible interactions of each compound with the Xanthine Oxidase (XO) enzyme which is responsible for ROS generation and the obtained results show that these derivatives exhibit high binding affinities to the active site of the XO enzyme. Finally, the studied compounds satisfy both Lipinski and Veber druglikeness properties and could be considered as good radical scavengers.