Unraveling the antioxidant and prooxidant mechanisms of methyl pro-lithospermate: a DFT and thermodynamic analysis in polar media.

CONTEXT: Methyl pro-lithospermate (MPL) is a phenolic acid isolated from Salvia yunnanensis with documented neuroprotective properties, yet its fundamental antioxidant and prooxidant mechanisms remain poorly characterized. Understanding the thermochemical basis of its radical-scavenging activity, the influence of heterodimer formation with bioactive phenolic compounds (zingerone (ZG), catechin (CT)), and its capacity to modulate redox-active metal ions is essential for evaluating its therapeutic potential. This study systematically investigates the thermodynamic descriptors governing the antioxidant activity of MPL and its heterodimers (MPL-ZG, MPL-CT) in polar solvents (DMSO, methanol, water), alongside assessments of prooxidant potential and hydrophobicity.

METHODS

Density functional theory at the B3LYP-D3BJ/6-311++G(d,p)//6-31+G(d) level was employed, with solvation effects modeled using the SMD continuum approach as implemented in the GAUSSIAN16 package. Visualization of non-covalent interactions was performed using the reduced density gradient (RDG) analysis implemented in the Multiwfn software package, with molecular graphics generated using VMD. The thermodynamic descriptors for the three principal radical-scavenging mechanisms were computed, each in both enthalpic and free energy forms: The hydrogen atom transfer (HAT) mechanism, the sequential electron transfer proton transfer (SET-PT) mechanism, and the sequential proton loss electron transfer (SPLET) mechanism. The thermochemistry of radical scavenging was evaluated for each mechanism with the reactive species NO•, NOO•, ONOO•, HO•, HOO•, and DPPH•. Prooxidant potential was assessed via the standard redox potential derived from solvation-corrected free energies, and hydrophobicity was estimated through fragment-based calculation of the octanol-water partition coefficient (log P).