Natural Chain-Breaking Antioxidant and their Synthetic Analogs as Modulator of Oxidative Stress

Oxidative stress is associated with the increased production of reactive oxygen species orwith a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense.The penetration of oxygen and free radicals in the hydrophobic interior of biological membranesinitiates radical disintegration of the hydrocarbon "tails" of the lipids. This process is known as"lipid peroxidation", and the accumulation of the oxidation products as peroxides and the aldehydes and acids derived from them are often used as a measure of oxidative stress levels. In total,40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breakingantioxidant activity, and thus as modulators of oxidative stress. This included natural and naturallike ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methodssuch as density functional theory (DFT) and quantitative structure-activity relationship ((Q)SAR)modeling) were used to clarify their structure-activity relationship. Kinetics of non-inhibited andinhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress isconsidered. Special attention has been paid to chemical reactions resulting in the initiation of freeradicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolicring of hydroxylated phenols and biphenols, and the concentration were discussed.