Novel anti-neuroinflammatory pyranone-carbamate derivatives as selective butyrylcholinesterase inhibitors for treating Alzheimer's disease.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chuanyu Yu, Xueyan Liu, Bingxiang Ma, Jiexin Xu, Yiquan Chen, Chaoxian Dai, Huaping Peng, Daijun Zha
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Abstract

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound 7p exhibited balanced BuChE inhibitory activity (eqBuChE IC50 = 4.68 nM; huBuChE IC50 = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound 7p was a mix-type BuChE inhibitor. Additionally, compound 7p displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound 7p had good safety in vivo as verified by an acute toxicity assay (LD50 > 1000 mg/kg). Most importantly, compound 7p effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound 7p could serve as a promising lead compound for treating AD.

作为选择性丁酰胆碱酯酶抑制剂治疗阿尔茨海默病的新型抗神经炎吡喃酮-氨基甲酸酯衍生物。
丁酰胆碱酯酶(BuChE)和神经炎症最近已成为阿尔茨海默病(AD)的有希望的治疗方向。在此,我们合成了 19 种新型吡喃酮-氨基甲酸酯衍生物,并评估了它们对胆碱酯酶和神经炎症的活性。最佳化合物 7p 表现出平衡的 BuChE 抑制活性(eqBuChE IC50 = 4.68 nM;huBuChE IC50 = 9.12 nM)和抗神经炎活性(10 μM 时 NO 抑制率 = 28.82%,与氢化可的松相当)。酶动力学和对接研究证实化合物 7p 是一种混合型 BuChE 抑制剂。此外,化合物 7p 在硅预测中显示出良好的药物相似性,并在 PAMPA-BBB 试验中表现出较高的 BBB 渗透性。经急性毒性实验验证,化合物 7p 在体内具有良好的安全性(半数致死剂量大于 1000 毫克/千克)。最重要的是,在东莨菪碱诱导的小鼠模型中,化合物 7p 能有效缓解认知和记忆障碍,其效果与利伐斯的明相当。因此,我们认为化合物 7p 有望成为治疗注意力缺失症的先导化合物。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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