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Discovery of novel hybrids containing clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease by Xinnan Li; Tiantian Li; Pengfei Zhang; Xinuo Li; Li Lu; Yuan Sun; Bocheng Zhang; Stephanie Allen; Lisa White; James Phillips; Zheying Zhu; Hequan Yao; Jinyi Xu is a Chemistry article available to read on EtoBox.

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

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 Aβ 1–42-induced) and suppressed inflammation induced by Aβ 1–42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innova

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Author

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

Publisher

Elsevier BV

Published

2022

Language

EN

Field

Chemistry (Physical Sciences)