2. Academic Validation
  3. Design of N-salicyltryptamines-based highly selective BChE inhibitors to elevate brain acetylcholine, improve learning, and reduce amyloid-β in Alzheimer's disease

Design of N-salicyltryptamines-based highly selective BChE inhibitors to elevate brain acetylcholine, improve learning, and reduce amyloid-β in Alzheimer's disease

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118273. doi: 10.1016/j.ejmech.2025.118273.
Kun Wu 1,  Changlei Yang 1,  Jing Zeng 1,  Qingling Wu 1,  Yarong Zhao 1,  Chengxuan Hu 1,  Yuting Zhao 1,  Junbo Wu 2,  Heng Yang 3,  Zhen Wang 4,  Xue Peng 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 Department of Colorectal Surgery, Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital, Hengyang, 421001, Hunan, China.
  • 3 School of Pharmaceutical Science, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Science, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Oncology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, 810008, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, China. Electronic address: [email protected].
  • 5 School of Pharmaceutical Science, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
PMID: 41161056 DOI: 10.1016/j.ejmech.2025.118273
Abstract

Neurodegenerative diseases (NDDs) merges conserved mechanisms with disease-specific pathology. A dual-targeting approach, featuring a core scaffold for conserved pathological pathways and modular disease-specific pharmacophores could provide a systematic therapeutic framework for NDDs. Herein, we synthesized a series of N-salicyltryptamines-carbamate derivatives by appending AD specific BChE-targeted carbamate pharmacophores to anti-inflammatory carrier scaffolds M11/18 with NMe2 substituent on N-salicyloyl tryptamine derivatives. Among them, compound 17 exhibits picomolar BChE inhibition and exceptional selectivity (eqBChE IC50 = 7.44 × 10-5 ± 1.55 × 10-6 μM; SI = 270,000; hBChE IC50 = 1.48 × 10-3 ± 1.3 × 10-4 μM). In vitro and in vivo studies demonstrated 17 exhibited excellent COX-2 inhibitory activity (IC50 = 0.11 ± 0.01 μM), excellent blood-brain barrier permeability (Pe = 7.18 × 10-6 cm/s) and neuroprotective. Besides, ameliorated scopolamine-induced cognitive deficits superior to rivastigmine. Crucially, 17 demonstrated greater acetylcholine elevation than rivastigmine in mice brain, attributable to its highly selective BChE inhibition. This study identifies 17 as a promising AD therapeutic candidate and validates the potential of the N-Salicyltryptamines-based dual-targeting approach.

Keywords

Alzheimer's disease; Carbamate; Highly selective BChE inhibitor; Neurodegenerative diseases; Neuroinflammatory.

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