Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activiti...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2023-12, Vol.38 (1), p.2169682
Main Authors: Chen, Hongsong, Mi, Jing, Li, Sen, Liu, Zhengwei, Yang, Jing, Chen, Rui, Wang, Yujie, Ban, Yujuan, Zhou, Yi, Dong, Wu, Sang, Zhipei
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Acetylcholinesterase - metabolism
Aluminum chloride
Alzheimer Disease - drug therapy
Alzheimer's disease
Amyloid beta-Peptides
Animal sciences
Animals
Anti-inflammatory agents
Brain research
Carbamates - pharmacology
Cell injury
Chemistry
Chloride
Cholinesterase Inhibitors - pharmacology
Drug Design
Engineering
Enzymes
Hydroxyquinolines
Inflammation
Ligands
Microsomes
Molecular Structure
multifunctional agent
Neurodegenerative diseases
Neuroprotection
Neuroprotective Agents
Pharmaceuticals
Pheochromocytoma cells
quinoline-O-carbamate derivatives
Quinolines - pharmacology
Research Paper
Structure-Activity Relationship
Toxicology
Tumor necrosis factor-TNF
Zebrafish
zebrafish AD model
Zoology
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Summary:A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC 50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on Aβ 25-35 -induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl 3 -induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2023.2169682