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

Mengzhen Li; Chao Ma; Yao Li; Hanxun Wang; Xiaomeng Xiu; Xueqi Zhao; Peng Liu; Huali Yang; Maosheng Cheng

doi:10.1016/j.ejmech.2024.117198

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

Eur J Med Chem. 2024 Dec 24:284:117198. doi: 10.1016/j.ejmech.2024.117198. Online ahead of print.

Authors

Mengzhen Li¹, Chao Ma¹, Yao Li¹, Hanxun Wang¹, Xiaomeng Xiu¹, Xueqi Zhao¹, Peng Liu², Huali Yang³, Maosheng Cheng⁴

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 Aβ_1-42 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.