Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives

Xu, Yang; Shen, Hong; Liu, Youxia; Cao, Yuan; Huang, Jingjing; Yan, Pu; Wei, Yongbiao; Zhao, Zhenwen; Liu, Xiangjun; Shangguan, Dihua

doi:10.3390/ijms27188262

Open AccessArticle

Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives

by

Yang Xu

^1,2,3,†,

Hong Shen

^4,†

,

Youxia Liu

^1,2,

Yuan Cao

^1,2,

Jingjing Huang

^1,5,

Pu Yan

^1,2,

Yongbiao Wei

⁵,

Zhenwen Zhao

^1,2

,

Xiangjun Liu

^1,2,* and

Dihua Shangguan

^1,2,3,*

¹

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

²

School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

³

School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310013, China

⁴

Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing 100034, China

⁵

Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Guangxi Medical University, No. 22, Shuangyong Road, Nanning 530021, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(18), 8262; https://doi.org/10.3390/ijms27188262

Submission received: 31 July 2026 / Revised: 9 September 2026 / Accepted: 13 September 2026 / Published: 16 September 2026

(This article belongs to the Special Issue From Drug Design to Mechanistic Understanding and Resistance)

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Abstract

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.

Keywords: caffeic acid amide derivatives; N-heterocycle; antitumor activity; antioxidant; anti-inflammatory; neuroprotection

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MDPI and ACS Style

Xu, Y.; Shen, H.; Liu, Y.; Cao, Y.; Huang, J.; Yan, P.; Wei, Y.; Zhao, Z.; Liu, X.; Shangguan, D. Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives. Int. J. Mol. Sci. 2026, 27, 8262. https://doi.org/10.3390/ijms27188262

AMA Style

Xu Y, Shen H, Liu Y, Cao Y, Huang J, Yan P, Wei Y, Zhao Z, Liu X, Shangguan D. Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives. International Journal of Molecular Sciences. 2026; 27(18):8262. https://doi.org/10.3390/ijms27188262

Chicago/Turabian Style

Xu, Yang, Hong Shen, Youxia Liu, Yuan Cao, Jingjing Huang, Pu Yan, Yongbiao Wei, Zhenwen Zhao, Xiangjun Liu, and Dihua Shangguan. 2026. "Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives" International Journal of Molecular Sciences 27, no. 18: 8262. https://doi.org/10.3390/ijms27188262

APA Style

Xu, Y., Shen, H., Liu, Y., Cao, Y., Huang, J., Yan, P., Wei, Y., Zhao, Z., Liu, X., & Shangguan, D. (2026). Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives. International Journal of Molecular Sciences, 27(18), 8262. https://doi.org/10.3390/ijms27188262

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Synthesis and Biological Activity Assessment of Caffeic Acid Azaheterocyclic Amide Derivatives

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