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

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Mengzhen Li , Chao Ma , Yao Li , Hanxun Wang , Xiaomeng Xiu , Xueqi Zhao , Peng Liu , Huali Yang , Maosheng Cheng
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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.

Abstract Image

Abstract Image

加兰他明类似物对阿尔茨海默病认知改善的设计、合成和生物学评价
加兰他敏在脑部疾病的治疗中起着至关重要的作用。本研究设计、合成并评价了一系列加兰他明类似物作为阿尔茨海默病(AD)的潜在治疗药物。通过在加兰他明的羟基上引入苄基吡啶环,得到了胆碱酯酶双抑制剂C2。与加兰他明(hAChE, IC50 = 1529±6 nM)相比,C2对hAChE (IC50 = 513.90±9.60 nM)和hBuChE (IC50 = 357.77±10.24 nM)具有较好的抑制活性。进一步的研究表明,C2具有显著的保护PC12细胞免受h2o2诱导的凋亡和活性氧(ROS)产生的能力。体内急性毒性试验表明,C2具有显著的安全性。无论是Aβ1-42模型引起的急性记忆障碍,还是东莨菪碱模型引起的遗忘,口服C2对认知和空间记忆的改善效果均优于口服C2。综上所述,体外和体内实验结果表明,C2作为抗ad药物值得进一步探索。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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