Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives

Natural caffeic acid derivatives are ubiquitous plant phenolic compounds with documented antitumor, antioxidant, and anti-inflammatory bioactivities. However, their clinical application is limited by low bioactivity potency and poor stability. Therefore, rational design and synthesis of novel caffeic acid derivatives are critical to improve their druglikeness and broaden biomedical applications. Herein, fourteen amide derivatives (H1-H14) were synthesized by conjugating three 3,4-substituted caffeic acid skeletons with five nitrogen-containing heterocycles. Bioactivity evaluation revealed that these derivatives exhibited structure- and cell-dependent biological profiles. Among them, compounds H8 and H13 containing 5-methoxytryptamine exerted the most potent antitumor activity by suppressing DNA and RNA synthesis and arresting the cell cycle at the G2/M phase. Derivatives with a catechol moiety (H11-H14) possessed prominent antioxidant activity, while H11 and H12, containing morpholine and 1-methylpiperazine respectively, exhibited remarkable anti-inflammatory activity. Compound H5 also presented significant protective effects against H₂O₂-induced neuronal injury. The cellular uptake assay revealed a correlation with clogP values: derivatives with clogP > 2.5 showed higher cellular internalization. Collectively, nitrogen-containing heterocyclic moieties and 3,4-substitution effectively modulate the multiple bioactivities of caffeic acid derivatives, providing valuable guidance for further structural optimization and drug development.