Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine

Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 mu M onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease. (C) 2014 Elsevier Masson SAS. All rights reserved.