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

Liu, Yulin; Uras, Giuseppe; Onuwaje, Itse; Li, Wenlong; Yao, Hong; Xu, Shengtao; Li, Xinuo; Li, Xinnan; Phillips, James; Allen, Stephanie; Gong, Qi; Zhang, Haiyan; Zhu, Zheying; Liu, Jie; Xu, Jinyi

Abstract

A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Aβ 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 = 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.

Citation

Liu, Y., Uras, G., Onuwaje, I., Li, W., Yao, H., Xu, S., Li, X., Li, X., Phillips, J., Allen, S., Gong, Q., Zhang, H., Zhu, Z., Liu, J., & Xu, J. (2022). Novel inhibitors of AChE and Aβ aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 235, Article 114305. https://doi.org/10.1016/j.ejmech.2022.114305

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2022
• Online Publication Date: Mar 24, 2022
• Publication Date: May 5, 2022
• Deposit Date: Apr 5, 2022
• Publicly Available Date: Mar 25, 2023
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 235
• Article Number: 114305
• DOI: https://doi.org/10.1016/j.ejmech.2022.114305
• Keywords: Organic Chemistry; Drug Discovery; Pharmacology; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/7709148
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523422002070?via%3Dihub