Affordable Access

Publisher Website

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

Authors
  • Li, Xinnan1
  • Li, Tiantian2
  • Zhang, Pengfei1
  • Li, Xinuo1
  • Lu, Li2
  • Sun, Yuan1
  • Zhang, Bocheng2
  • Allen, Stephanie2
  • White, Lisa2
  • Phillips, James3
  • Zhu, Zheying4
  • Yao, Hequan5
  • Xu, Jinyi6
  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. , (China)
  • 2 School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.
  • 3 School of Pharmacy, University College London, London, WC1N 1AX, UK.
  • 4 School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK. Electronic address: [email protected].
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: [email protected]. , (China)
  • 6 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: [email protected]. , (China)
Type
Published Article
Journal
European journal of medicinal chemistry
Publication Date
Dec 15, 2022
Volume
244
Pages
114841–114841
Identifiers
DOI: 10.1016/j.ejmech.2022.114841
PMID: 36257284
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Report this publication

Statistics

Seen <100 times