Spirocyclic pyridoazepine analogues of galanthamine: Synthesis, modelling studies and evaluation as inhibitors of acetylcholinesterase

Abstract

Spirocyclic pyridoazepines, designed as simplified analogues of the alkaloid galanthamine, were synthesised and evaluated as inhibitors of acetylcholinesterase. The key cyclisation step involved internal displacement of 2-chloro or 2-iodopyridine by either nucleophilic aromatic substitution or a Heck reaction. The target compounds showed significant inhibition of acetylcholinesterase but lower than that of galanthamine. This result could be rationalised by comparative docking simulation studies based on the known crystal structure of the acetylcholinesterase-galanthamine complex; multiple hydrogen bonding of a cocrystallised water molecule to both the receptor and the ligand was found to be of crucial importance for effective binding to the active site of the enzyme. © Wiley-VCH Verlag GmbH & Co. KGaA, 2008.