Theoretical exploration of iseluxine as a promising natural antioxidant.

CONTEXT: Iseluxine (ISL), an isoquinolinone alkaloid derived from Iseia luxurians, exhibits remarkable antioxidant potential, surpassing conventional antioxidants such as vitamin C and BHA in vitro. To clarify its radical-scavenging behavior, density functional theory (DFT) calculations were conducted against key reactive oxygen and nitrogen species (ROS and RNS), including HO•, CH₃O•, CH₃OO•, HOO•, NO•, NO₂•, and O₂•-. Three mechanisms, formal hydrogen atom transfer (fHAT), sequential electron transfer-proton transfer (SETPT), and sequential proton loss-electron transfer (SPLET) were examined in gas, water, and lipid-like (pentylethanoate) media. Thermodynamic analysis identified the O6-H bond as the most reactive site due to its low bond dissociation enthalpy and proton affinity. Kinetic modeling indicated efficient HOO• scavenging via the SET pathway in water, with a rate constant of 1.8 × 106 M⁻1 s⁻1, significantly higher than that of Trolox. ISL also showed strong activity against CH₃O•, CH₃OO•, and NO₂, but limited reactivity toward NO, and O₂•-, emphasizing its selective antioxidant potential.

METHODS

Density functional theory (DFT) calculations were performed using the M06-2X functional with the 6-31G(d,p)//6-311 +  + G(d,p) basis set for single-point energy, geometry optimizations and kinetic calculations. Thermodynamic and kinetic parameters were obtained following the QM-ORSA protocol, combined with the SMD solvation model to simulate aqueous and pentylethanoate media.