Citation: Qiyao Zhang, Yuting Li, Qishun Jin, Zhengwei Liu, Hongsong Chen, Jingqi Huang, Taoyi Liu, Xiaojuan Liu, Zhenghuai Tan, Shuheng Huang, Wu Dong, Zhipei Sang. Artificial intelligence-driven development of natural multi-target derivatives with BuChE inhibitory activity for treating Alzheimer’s disease[J]. Chinese Chemical Letters, ;2026, 37(1): 110964. doi: 10.1016/j.cclet.2025.110964 shu

Artificial intelligence-driven development of natural multi-target derivatives with BuChE inhibitory activity for treating Alzheimer’s disease

Qiyao Zhang ^{a, b, 1} ,
Yuting Li ^{a, c, 1} ,
Qishun Jin ^{a, 1} ,
Zhengwei Liu ^{a, d, 1} ,
Hongsong Chen ^e ,
Jingqi Huang ^a ,
Taoyi Liu ^a ,
Xiaojuan Liu ^a ,
Zhenghuai Tan ^f ,
Shuheng Huang ^{a, *,} ,
Wu Dong ^{e, *,} ,
Zhipei Sang ^{a, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
School of Food Science and Engineering, Hainan University, Haikou 570228, China
c.
School of Life and Health Sciences, Hainan University, Haikou 570228, China
d.
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
e.
College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao 028000, China
f.
Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China

shhuang@hainanu.edu.cn

dongwu@imun.edu.cn

sangzhipei@hainanu.edu.cn

Received Date: 9 December 2024
Revised Date: 14 February 2025
Accepted Date: 17 February 2025
Available Online: 17 February 2025

Figures(5)

Alzheimer’s disease (AD) is a common neurodegenerative disorder among the elderly population. There are currently no effective therapeutic drugs available, the multi-target-directed ligands (MTDLs) strategy has been considered as the promising approach. Given the structural diversity of natural products, Rivastigmine’s pharmacophore was integrated with diverse natural product scaffolds to construct a combinatorial compound library. This library was subsequently screened and optimized to identify a novel butyrylcholinesterase (BuChE) inhibitor, compound 3c. The results showed that compound 3c exhibited favorable BuChE inhibitory activity (half-maximal inhibitory concentration (IC₅₀) = 0.43 µmol/L), potential anti-inflammatory potency, good Aβ_1–42 aggregation inhibitory capacity and remarkable neuroprotective effects. The in vivo study exhibited that 3c significantly ameliorated AlCl₃-induced zebrafish AD model and scopolamine-induced memory impairment. Collectively, compound 3c was the artificial intelligence (AI)-driven promising multifunctional agent with BuChE inhibition for the treatment of AD.
- Alzheimer’s disease,
- AI-driven,
- Multifunctional agents,
- BuChE inhibitor,
- In vivo study
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沈阳化工大学材料科学与工程学院沈阳 110142