Mechanistic Insights into the Antioxidant Activity of Baicalein and Related Flavones: A DFT and Molecular Dynamics Study

This study presents a comprehensive density functional theory (DFT) investigation of the antioxidant mechanisms of baicalein and four related flavones: chrysin, wogonin, norwogonin, and oroxylin A. Using the M06-2X/6-311+G(d,p) level of theory, we evaluated their radical scavenging potentials through multiple thermodynamic descriptors associated with different antioxidant pathways, including hydrogen atom transfer (HAT), sequential proton loss–electron transfer (SPLET), single electron transfer–proton transfer (SETPT), sequential proton loss–hydrogen atom transfer (SPLHAT), and double hydrogen atom transfer (dHAT). The conformational analysis revealed that intramolecular hydrogen bonding significantly stabilizes geometries, influencing reactivity. Among all investigated compounds, baicalein and norwogonin, each containing three phenolic groups, exhibited the most favourable bond dissociation enthalpies (BDEs), proton affinities (PAs) and ionisation potentials (IPs), particularly at the 6-OH and 8-OH positions, respectively. The study identifies key structure–activity relationships, emphasizing the role of hydroxyl positions and their count as well as phenyl ring in modulating antioxidant efficiency. Molecular dynamics-derived solubility profiles reveal the preferential compatibility of flavones with nonpolar solvents, emphasizing the critical influence of the phenyl ring in modulating their solubility behavior. These findings establish a theoretical foundation for the design of potent antioxidant compounds.