2. Academic Validation
  3. Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease

Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130478. doi: 10.1016/j.bmcl.2025.130478.
Tiancheng Sun 1,  Zhonghua Li 2,  Bingyu Xiao 1,  Jige Yang 1,  Mengyu Han 1,  Jiaxin Zhang 1,  Sijia Liu 1,  Jinlian Ma 3,  Pan Wang 4
Affiliations

Affiliations

  • 1 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
  • 2 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. Electronic address: [email protected].
  • 3 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
  • 4 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China. Electronic address: [email protected].
PMID: 41265581 DOI: 10.1016/j.bmcl.2025.130478
Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like Atractylodes macrocephala (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu2+-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy.

Keywords

Alzheimer's disease; Amyloid β; Atractylenolide; Atractylodes macrocephala.

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