期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 11, 页码 7483-7506出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00160
关键词
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资金
- National Natural Science Foundation of China [81874289, 81903446]
- The Open Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMKF 201710]
- Natural Science Foundation of Jiangsu Province [BK20190564]
- China Postdoctoral Science Foundation [2019M652037]
- Double First-Class University Project [CPU2018GY04, CPU2018GY35]
- China Pharmaceutical University
- School of Pharmacy, The University of Nottingham [RJ/T5433]
A series of novel tacrine-pyrimidone hybrids showed significant inhibitory activities against AChE and GSK-3. The optimal compound 27g exhibited dual AChE/GSK-3 inhibition, cognitive improvement, and neuroprotection, making it a promising lead for AD treatment.
Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3 beta: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
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