Single molecule, dual actions: GSK-3β/AChE dual inhibition for Alzheimer's disease

  • Eur J Med Chem. 2026 Oct 15:316:119075. doi: 10.1016/j.ejmech.2026.119075.
Li Dong  1 ,  Jing Yang  1 ,  Yunniao Meng  1 ,  Sisi Yang  1 ,  Changluan Pan  1 ,  Fangxing Luo  1 ,  Haiyan Long  1 ,  Shaofang Lv  1 ,  Yaozhen Gong  1 ,  Juan Xu  2 ,  Ying Xiong  3 ,  Yongxi Dong  4
Affiliations
  • 1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guian New District, 561113, China.
  • 2. School of Public Health, Guizhou Medical University, Guian New District, 561113, China. Electronic address: [email protected].
  • 3. School of Basic Medical Sciences, Guizhou Medical University, Guian New District, 561113, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guian New District, 561113, China. Electronic address: [email protected].
PMID: 42320199 DOI: 10.1016/j.ejmech.2026.119075
Abstract

The pathogenesis of Alzheimer's Disease (AD) is closely related with glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3β inhibitory and neuroprotective activities relative to Tideglusib. Accordingly, a molecular hybridization strategy was applied to design and synthesize a series of dual target inhibitors against GSK-3β and AChE by conjugating GL10a and carbamate fragment of Rivastigmine's pharmacophore. After in vitro evaluations, the compound AJ-4 was screened as the most remarkable compound with potent inhibitory activities against GSK-3β (IC50: 4.7 nM) and AChE (IC50: 2.97 μM). Meanwhile, in vitro and in vivo data revealed that the optimal compound AJ-4 with excellent enzyme selectivity could decrease amyloid precursor protein (APP) and phosphorylated Tau expressions and increase phosphorylated GSK-3β levels. With favorable pharmacokinetic characteristics and tissue distribution, AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments and alleviated hippocampal neuronal injury in AD mice. In conclusion, GSK-3β/AChE dual inhibitors represent a promising strategy for developing multi-target anti-AD drugs.

Keywords
Acetylcholinesterase; Alzheimer's disease; Dual inhibitors; GSK-3β; Molecular hybridization.
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