Thermodynamic and kinetic insights into the antiradical activity of epicoccone B: a computational study

Elucidating the radical scavenging mechanisms of bioactive natural products is essential for understanding their antioxidant performance under different physiological conditions. In this work, the antioxidant activity of epicoccone B (EB) was comprehensively explored in aqueous and pentylethanoate using a quantum chemical framework. Thermodynamic analysis indicates that EB possesses multiple reactive hydroxyl sites with distinct roles depending on the medium. In water, low proton affinity values, particularly at the O8–H position, favor the SPLET pathway, while the relatively low ionization energy supports the contribution of electron transfer processes. Kinetic results further demonstrate that the overall antioxidant activity is dominated by the SET mechanism of deprotonated species, yielding a high rate constant of 1.91 × 10⁶ M⁻¹ s⁻¹. Notably, this value is significantly higher than that of Trolox and comparable to or greater than several well-known antioxidants such as gallic acid and dopamine, highlighting the strong radical scavenging capacity of EB. In contrast, in pentylethanoate, increased PA and IP values suppress ionic mechanisms, and the reaction proceeds mainly via formal hydrogen atom transfer, with the O7–H bond identified as the most active site. Gibbs free energy calculations confirm that hydrogen transfer is thermodynamically preferred, particularly at the O1 position, and that reactivity decreases in less polar environments. These findings reveal a pronounced solvent-dependent antioxidant behavior and suggest that EB is significantly more effective in polar media.

All computations were carried out using density functional theory at the M06-2X/6–311 +  + G(d,p) level. Fully optimized geometries and vibrational frequency calculations were performed to ensure true minima and to obtain thermodynamic properties in both aqueous and pentylethanoate environments via an SMD implicit solvation model. Frontier thermodynamic parameters, including bond dissociation energies (BDEs), proton affinities (PAs), and ionization energies (IPs), were calculated to assess the feasibility of the fHAT, SPLET, and SETPT mechanisms. The acid–base behavior of EB was evaluated through pK_a calculations to determine species distribution under physiological conditions. Reaction kinetics toward the HOO• radical were investigated using the QM-ORSA approach to obtain activation free energies, rate constants, and pathway contributions. All calculations were performed using the Gaussian 09 software package.