Discovery of novel hybrids containing clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease

Li, Xinnan; Li, Tiantian; Zhang, Pengfei; Li, Xinuo; Lu, Li; Sun, Yuan; Zhang, Bocheng; Allen, Stephanie; White, Lisa; Phillips, James; Zhu, Zheying; Yao, Hequan; Xu, Jinyi

Abstract

Based on the multitarget strategy, a series of novel clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC50 = 0.11 μM), appropriate metal chelating functions, modulation of AChE- and metal-induced Aβ aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 μM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD50 = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Aβ1–42-induced) and suppressed inflammation induced by Aβ1–42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease.

Citation

Li, X., Li, T., Zhang, P., Li, X., Lu, L., Sun, Y., Zhang, B., Allen, S., White, L., Phillips, J., Zhu, Z., Yao, H., & Xu, J. (2022). Discovery of novel hybrids containing clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease. European Journal of Medicinal Chemistry, 244, Article 114841. https://doi.org/10.1016/j.ejmech.2022.114841

• Journal Article Type: Article
• Acceptance Date: Oct 8, 2022
• Online Publication Date: Oct 12, 2022
• Publication Date: Dec 15, 2022
• Deposit Date: Oct 17, 2022
• Publicly Available Date: Oct 13, 2023
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 244
• Article Number: 114841
• DOI: https://doi.org/10.1016/j.ejmech.2022.114841
• Keywords: Organic Chemistry; Drug Discovery; Pharmacology; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/12599391
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523422007437?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Discovery of novel hybrids containing clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2022.114841; Content Type: article; Copyright: © 2022 Elsevier Masson SAS. All rights reserved.