Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase.
A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridinium by a 2-carbon spacer, was found to be a potent inhibitor of AChE, with an IC(50) value of 0.048 microM and compound 40c, berberine linked with 2-thionaphthol by a 4-carbon spacer, acted as the most potent inhibitor for BuChE with an IC(50) value of 0.078 microM. Kinetic studies and molecular modeling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives.
Huang
Ling
L
The Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Luo
Zonghua
Z
He
Feng
F
Lu
Jing
J
Li
Xingshu
X
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C552772:9-O-((2-(3-methyl)pyridinium)ethyl)berberine; C552771:9-O-(3-(naphthalene-2-ylthio)butyl)berberine; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D001599:Berberine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase