Journal
BIOORGANIC CHEMISTRY
Volume 93, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103310
Keywords
Alzheimer's disease; Cholinesterase inhibitor; Quinoline-ferulic acid hybrid; Molecular docking
Funding
- National Natural Science Foundation of China [81872728, 81573281]
- Natural Science Foundation of Jiangsu Province [BK20191411]
- Double First-Classinitiative Innovation team project of China Pharmaceutical University [CPU2018GF11, CPU2018GY34]
- Jiangsu Qinglan Project
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A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50 = 0.62 +/- 0.17 mu M), and 14 was the most potent inhibitor against BChE (IC50 = 0.10 +/- 0.01 mu M). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
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