[Design, synthesis and evaluation of bis-nicotine derivatives as inhibitors of cholinesterases and beta-amyloid aggregation].
A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China. luowen83@henu.edu.cn
Wen
W
Luo
Pharmaceutical School of Henan Province, Kaifeng 475001, China.
Yong-mei
YM
Zhao
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
Run-guo
RG
Tian
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
Ya-bin
YB
Su
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
Chen
C
Hong
D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D009538:Nicotine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase