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Novel inhibitors of AChE and A0 aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease

文献类型：期刊论文

作者Liu, Yulin5,6,7; Uras, Giuseppe2,4; Onuwaje, Itse3; Li, Wenlong6,7; Yao, Hong6,7; Xu, Shengtao6,7; Li, Xinuo6,7; Li, Xinnan6,7; Phillips, James3; Allen, Stephanie4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-05-05
卷号235页码:22
ISSN号0223-5234
关键词Alzheimer's disease Donepezil Sulfone group AChE inhibitor Inhibiting A 0 aggregation Neuroprotection
DOI10.1016/j.ejmech.2022.114305
通讯作者Zhu, Zheying(zheying.zhu@nottingham.ac.uk) ; Liu, Jie(cpu-jill@163.com) ; Xu, Jinyi(jinyixu@china.com)
英文摘要A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting A0 aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC50 1/4 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents.
WOS关键词BENZYL PYRIDINIUM MOIETY ; BIOLOGICAL EVALUATION ; ACETYLCHOLINESTERASE INHIBITORS ; MULTIFUNCTIONAL AGENTS ; DESIGN ; DONEPEZIL ; DERIVATIVES ; POTENT ; HYBRIDS ; PATHOPHYSIOLOGY
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000793276100005
源URL[http://119.78.100.183/handle/2S10ELR8/301113]  
专题中国科学院上海药物研究所
通讯作者Zhu, Zheying; Liu, Jie; Xu, Jinyi
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
2.UCL, Dept Clin & Movement Neurosci, Queen Sq Inst Neurol, London, England
3.UCL, Sch Pharm, Dept Pharmacol, London, England
4.Univ Nottingham, Sch Pharm, Div Mol Therapeut & Formulat, Univ Pk, Nottingham NG7 2RD, England
5.China Pharmaceut Univ, Dept Organ Chem, Nanjing, Peoples R China
6.China Pharmaceut Univ, Dept Med Chem, Nanjing, Peoples R China
7.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Yulin,Uras, Giuseppe,Onuwaje, Itse,et al. Novel inhibitors of AChE and A0 aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,235:22.
APA Liu, Yulin.,Uras, Giuseppe.,Onuwaje, Itse.,Li, Wenlong.,Yao, Hong.,...&Xu, Jinyi.(2022).Novel inhibitors of AChE and A0 aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,235,22.
MLA Liu, Yulin,et al."Novel inhibitors of AChE and A0 aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 235(2022):22.

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来源：上海药物研究所

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