Rational design of caffeic acid amides as novel antioxidants in lipid systems: Experimental and theoretical studies

Caffeic acid (CA), known as a natural phenolic compound, is widely recognized for its antioxidant properties and potential applications in food preservation. However, its practical antioxidant efficacy and potential applications have been limited due to its poor lipophilicity. To overcome this issue, based on the hydrophobic residue structure and antioxidant activity of amino acids, three amino acids (methionine, tyrosine, and tryptophan) were screened for amidation with CA to both improve the lipophilicity of CA and enhance its antioxidant performance. The antioxidant efficacy of CA amides was evaluated by experimental and theoretical approach. The experimental results showed that CA amides with tryptophan exhibited the excellent antioxidant efficacy, which increased by 49 % and 47 % compared to CA in DPPH and FRAP assays, respectively. The induction period of lard with CA amides in the Rancimat test was increased by 45-55 % compared to CA. Density Functional Theory (DFT) analysis demonstrated that tryptophan conjugation improved the electron-donating ability (E_HOMO from -7.306 to -6.863 eV) and reduced the O-H bond dissociation energy (from 79 to 78 kcal/mol) of CA amide. Moreover, the 4-OH site was identified as the primary active site for radical scavenging. These results clarified how specific amino acid residues modulate the antioxidant behavior at the molecular level and indicated that CA amides with tryptophan were more effective in scavenging free radicals. These findings offer valuable insights into the structure-antioxidant activity relationship of CA amides, highlighting their potential as antioxidants and application in inhibiting lipid oxidation.