Phelligridin A as a promising antioxidant agent: a theoretical study using DFT

Phenolic compounds are widely recognized for their antioxidant potential, yet their radical-scavenging efficiency strongly depends on solvent polarity, protonation state, and underlying reaction mechanisms. In this work, the antioxidant activity of Phelligridin A (PheA) was systematically investigated to clarify its preferred reactive sites, dominant scavenging pathways, and kinetic efficiency toward the HOO· radical in polar and weakly polar environments. Thermodynamic analyses reveal that the phenolic 8-OH and 9-OH groups are the primary antioxidant centers, while the 4-C-H site is inactive. The results indicate a clear solvent dependence, with the formal hydrogen atom transfer mechanism favored in pentylethanoate and SPLET (sequential proton loss electron transfer) mechanism becoming more relevant in water. Kinetic evaluations show that PheA exhibits rapid radical-scavenging activity, particularly in aqueous solution where deprotonated species enhance the overall reaction rate, resulting in a rate constant approximately 15 times higher than that of Trolox, a widely used reference antioxidant. In addition, in silico ADMET profiling suggests that PheA possesses favorable drug-like properties and generally low toxicity, supporting its potential relevance as a bioactive antioxidant in polar biological environments.

All quantum-chemical calculations were performed using Gaussian 09. Geometry optimizations, thermodynamic parameters, and kinetic analyses were carried out at the M06-2X/6-311 +  + G(d,p) level of theory. Solvent effects for water and pentylethanoate were treated using the SMD implicit solvation model. Antioxidant mechanisms and rate constants were evaluated following the QM-ORSA protocol, including formal hydrogen atom transfer and single-electron transfer pathways, with intrinsic reaction coordinate calculations used to verify transition states. Frontier molecular orbital and molecular electrostatic potential analyses were conducted to assess electronic reactivity. Atom-in-molecule analyses were performed with the Multiwfn program. ADMET properties were predicted using the SwissADME, pkCSM, and ProTox 3.0 web-based platforms.