Synthesis and anticholinesterase activity of fumaramide derivatives

A series of fumaramide derivatives were synthesized from substituted benzanilines and their cholinesterase inhibitory activity was assayed according to Ellman's method using galanthamine-HBr as the reference compound. Most of the fumaramide compounds showed inhibitory activity of both cholinesterase enzymes. Compounds 29 (IC50 = 0.14 mu M) and 30 (IC50 = 16.50 mu M) were found to be the most active inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes, respectively. Molecular docking studies were performed with Surflex-Dock programme to provide the possible interactions between compounds and enzymes. A Lineweaver-Burk plot and molecular modelling studies showed that fumaramide compounds targeted both the catalytic anionic site and the peripheral anionic site of AChE. It was revealed that the nature of alpha,beta-unsaturated 1,4-diketone moiety in fumaramide compounds brought about useful and efficient modification especially on AChE inhibition.