Huang_2010_Bioorg.Med.Chem_18_4475

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.