Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 24, Issue 4, Pages 672-680Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.12.031
Keywords
Flavonoid derivatives; Cholinesterase; Anti-Alzheimer agent; Molecular modeling; Cytotoxicity
Funding
- Natural Science Foundation of China [21302041]
- Postdoctoral Science Foundation of China [2012M521391]
- Educational Commission of Henan Province [14A350008]
- Postdoctoral Science Foundation of Henan Province [2011015]
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A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4-Hchromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64 mu M for AChE and 0.42 mu M for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10 mu M. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease. (c) 2015 Elsevier Ltd. All rights reserved.
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