Discovery of Novel Tacrine–Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer’s Disease

Yao, Hong; Uras, Giuseppe; Zhang, Pengfei; Xu, Shengtao; Yin, Ying; Liu, Jie; Qin, Shuai; Li, Xinuo; Allen, Stephanie; Bai, Renren; Gong, Qi; Zhang, Haiyan; Zhu, Zheying; Xu, Jinyi

Abstract

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-3β: 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.

Citation

Yao, H., Uras, G., Zhang, P., Xu, S., Yin, Y., Liu, J., …Xu, J. (2021). Discovery of Novel Tacrine–Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer’s Disease. Journal of Medicinal Chemistry, 64(11), 7483-7506. https://doi.org/10.1021/acs.jmedchem.1c00160

• Journal Article Type: Article
• Acceptance Date: May 12, 2021
• Online Publication Date: May 23, 2021
• Publication Date: Jun 10, 2021
• Deposit Date: May 25, 2021
• Publicly Available Date: May 24, 2022
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society (ACS)
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Issue: 11
• Pages: 7483-7506
• DOI: https://doi.org/10.1021/acs.jmedchem.1c00160
• Keywords: Molecular Medicine; Drug Discovery
• Public URL: https://nottingham-repository.worktribe.com/output/5572177
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00160
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00160