2. Academic Validation
  3. Discovery of a highly selective BChE inhibitor with concomitant anti-neuroinflammatory activity for treating Alzheimer's disease

Discovery of a highly selective BChE inhibitor with concomitant anti-neuroinflammatory activity for treating Alzheimer's disease

  • Eur J Med Chem. 2025 Dec 5:299:118071. doi: 10.1016/j.ejmech.2025.118071.
Yarong Zhao 1,  Kun Wu 1,  Wei Luo 1,  Yuting Zhao 1,  Jing Zeng 1,  Junbo Wu 2,  Changlei Yang 1,  Meiling Yang 3,  Jia Liu 1,  Zhengwen Lei 4,  Xue Peng 5,  Zhen Wang 6
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 Department of Oncology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4 Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: leizhengwen0803@163.com.
  • 5 School of Pharmaceutical Science, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: pengxue@usc.edu.cn.
  • 6 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: zhenw@usc.edu.cn.
PMID: 40884959 DOI: 10.1016/j.ejmech.2025.118071
Abstract

Recently, butyrylcholinesterase (BChE) has emerged as a potential therapeutic target for advanced Alzheimer's disease (AD). Herein, 20 novel carbamate-based N-benzoyl tryptamine derivatives were designed and synthesized by integrating a BChE-targeting fragment with the original carrier scaffold, which possesses good anti-neuroinflammatory activity. Among them, N14 was proved to be the most potent and highly selective BChE Inhibitor [eqBChE IC50 = 18.00 ± 0.485 pM, selectivity index (SI) = 84,7252, hBChE IC50 = 1.50 ± 0.155 nM], which is 388 times greater than the BChE Inhibitor previously identified by our research group. Additionally, N14 showed superior neuroprotective effects against Aβ1-42-induced injury model and inhibitory effects on Aβ1-42 self-aggregation compared to rivastigmine. Moreover, N14 could significantly ameliorate scopolamine-induced cognition impairment. Notably, N14 exhibited a superior capacity in the regulation of BChE and acetylcholine levels in the mouse hippocampus compared to rivastigmine, indicating that a highly selective BChE Inhibitor possesses more pronounced efficacy to rectify cholinergic system dysfunction. Furthermore, N14 demonstrated a high safety profile, good pharmacokinetic properties and favorable BBB permeability in vivo. Especially, N14 had a 3-fold longer half-life T1/2 than the BChE Inhibitor developed by our group. Therefore, the highly selective BChE Inhibitor N14 is a promising multifunctional lead compound for treating AD.

Keywords

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

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