Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors.
A new series of flavonoid derivatives have been designed, synthesised and evaluated as acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. Among them, fifteen derivatives were found to inhibit the enzyme in the micromolar range and isoflavone derivatives possessed more potent inhibitory activity than other flavonoid derivatives. The best compound 9a had its inhibitory activity (IC(50) = 0.093 microM) in the same range as the reference compound, donepezil (IC(50) = 0.025 microM). Preliminary structure-activity relationships and a molecular modeling study for 9a have revealed that the isoflavone moiety plays a key role in the interaction of this series of derivatives with AChE by acting as an anchor in its peripheral anionic site.
Shen
Yanhong
Y
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China.
Zhang
Jing
J
Sheng
Rong
R
Dong
Xiaowu
X
He
Qiaojun
Q
Yang
Bo
B
Hu
Yongzhou
Y
D000110:Acetylcholinesterase / Q000378:metabolism*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D005419:Flavonoids; D000110:Acetylcholinesterase