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

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.