2. Academic Validation
  3. Design, synthesis and biological evaluation of galantamine analogues for cognitive improvement in Alzheimer's disease

Design, synthesis and biological evaluation of galantamine analogues for cognitive improvement in Alzheimer's disease

  • Eur J Med Chem. 2025 Feb 15:284:117198. doi: 10.1016/j.ejmech.2024.117198.
Mengzhen Li 1,  Chao Ma 1,  Yao Li 1,  Hanxun Wang 1,  Xiaomeng Xiu 1,  Xueqi Zhao 1,  Peng Liu 2,  Huali Yang 3,  Maosheng Cheng 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China. Electronic address: pengliu@syphu.edu.cn.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016, China. Electronic address: yanghl@syphu.edu.cn.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016, China. Electronic address: mscheng@syphu.edu.cn.
PMID: 39733484 DOI: 10.1016/j.ejmech.2024.117198
Abstract

Galantamine plays a crucial role in the management of brain disorders. In this study, a series of galantamine analogues were designed, synthesized and evaluated as potential therapeutic agents for Alzheimer's disease (AD). Compound C2, a dual inhibitor of cholinesterase, was obtained by introducing a benzylpyridine ring to the hydroxyl group of galantamine. Compared to galantamine (hAChE, IC50 = 1529 ± 6 nM), C2 exhibited excellent inhibitory activities against hAChE (IC50 = 513.90 ± 9.60 nM) and hBuChE (IC50 = 357.77 ± 10.24 nM). Further studies revealed that C2 possessed significant abilities to protect PC12 cells from H2O2-induced Apoptosis and Reactive Oxygen Species (ROS) production. The acute toxicity test in vivo indicated that C2 exhibited a remarkable safety profile. Whether in the acute memory impairment induced by the Aβ1-42 model or in the amnesia induced by the scopolamine model, oral administration of C2 demonstrated superior improvement on cognition and spatial memory. In summary, both in vitro and in vivo results suggest that C2 deserves to be further explored as an anti-AD agent.

Keywords

Alzheimer's disease; Antioxidant; Cholinesterase inhibitors; Cognitive improvement; Galantamine.

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