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<p>In this work, 30 novel ester derivatives formed by conjugating tyrosol (Ty) or hydroxytyrosol (HT) with 15 common phenolic acids were theoretically designed, and their antioxidant activities were systematically evaluated using density functional theory (DFT). Three primary antioxidant mechanisms—hydrogen atom transfer (HAT), single-electron transfer coupled with proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET)—were investigated via calculations of key thermodynamic parameters, including bond dissociation enthalpy (BDE) of hydroxyl groups, ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE). The results demonstrated that esterification generally enhanced the antioxidant activity of <b>Ty</b> and <b>HT</b>, with hydroxytyrosol derivatives (HTDs) generally outperforming tyrosol derivatives (TyDs) due to the cooperative effects of additional phenolic hydroxyl groups. Among all derivatives, chlorogenic acid-conjugated compounds (XIV-Ty-4 and XIV-HT-4) exhibited superior antioxidant activity across all three mechanisms. Thermodynamically, HAT mechanism is favorable in the gas phase and two solvents, whereas solvation effects significantly reduce the energy barrier associated with all three antioxidant mechanisms. FMO analysis revealed that the hydroxyl groups of the phenolic acid moiety (especially chlorogenic acid) were the primary active sites, with narrow highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gaps enhancing reactivity. The results demonstrated that the antioxidant activity of these derivatives was mechanism dependent. XIV-Ty-4 and XIV-HT-4 exhibited the lowest BDE values, indicating superior hydrogen atom donation capability. In the SET-PT mechanism, XI-Ty and VII-HT displayed the lowest IP values, reflecting enhanced electron-donating ability, whereas VI-Ty-2 and III-HT-3′ exhibited the lowest PDE values, suggesting improved proton-coupled electron transfer efficiency. For the SPLET mechanism, XIV-Ty-1′ and XIV-HT-3′ possessed the lowest PA values, indicating strong proton transfer potential, while IV-Ty-2 and IV-HT-2 showed the lowest ETE values, highlighting superior sequential proton loss electron transfer activity. Collectively, XIV-Ty-4 and XIV-HT-4 consistently demonstrated more prominent antioxidant activity across all three mechanisms, making them promising candidates for high-performance natural antioxidants. These findings provide valuable theoretical guidance for the rational design of <b>Ty/HT</b> ester derivatives and the development of novel natural antioxidant candidates.</p>

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Theoretical evaluation of antioxidant mechanisms for ester derivatives of tyrosol/hydroxytyrosol and phenolic acids: identifying candidates with enhanced antioxidant activity

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Jun Lu,
  • Bai-Ze Liu,
  • Qing-Hua Lu,
  • Xiao-Jun Li,
  • Guo-Ze Wang

摘要

In this work, 30 novel ester derivatives formed by conjugating tyrosol (Ty) or hydroxytyrosol (HT) with 15 common phenolic acids were theoretically designed, and their antioxidant activities were systematically evaluated using density functional theory (DFT). Three primary antioxidant mechanisms—hydrogen atom transfer (HAT), single-electron transfer coupled with proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET)—were investigated via calculations of key thermodynamic parameters, including bond dissociation enthalpy (BDE) of hydroxyl groups, ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE). The results demonstrated that esterification generally enhanced the antioxidant activity of Ty and HT, with hydroxytyrosol derivatives (HTDs) generally outperforming tyrosol derivatives (TyDs) due to the cooperative effects of additional phenolic hydroxyl groups. Among all derivatives, chlorogenic acid-conjugated compounds (XIV-Ty-4 and XIV-HT-4) exhibited superior antioxidant activity across all three mechanisms. Thermodynamically, HAT mechanism is favorable in the gas phase and two solvents, whereas solvation effects significantly reduce the energy barrier associated with all three antioxidant mechanisms. FMO analysis revealed that the hydroxyl groups of the phenolic acid moiety (especially chlorogenic acid) were the primary active sites, with narrow highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gaps enhancing reactivity. The results demonstrated that the antioxidant activity of these derivatives was mechanism dependent. XIV-Ty-4 and XIV-HT-4 exhibited the lowest BDE values, indicating superior hydrogen atom donation capability. In the SET-PT mechanism, XI-Ty and VII-HT displayed the lowest IP values, reflecting enhanced electron-donating ability, whereas VI-Ty-2 and III-HT-3′ exhibited the lowest PDE values, suggesting improved proton-coupled electron transfer efficiency. For the SPLET mechanism, XIV-Ty-1′ and XIV-HT-3′ possessed the lowest PA values, indicating strong proton transfer potential, while IV-Ty-2 and IV-HT-2 showed the lowest ETE values, highlighting superior sequential proton loss electron transfer activity. Collectively, XIV-Ty-4 and XIV-HT-4 consistently demonstrated more prominent antioxidant activity across all three mechanisms, making them promising candidates for high-performance natural antioxidants. These findings provide valuable theoretical guidance for the rational design of Ty/HT ester derivatives and the development of novel natural antioxidant candidates.