Spirocyclic Pyridoazepine Analogues of Galanthamine: Synthesis, Modelling Studies and Evaluation as Inhibitors of Acetylcholinesterase

Autor:	Frans Compernolle, Arnout Voet, Sofie Vanlaer, Marc De Maeyer, Wim M. De Borggraeve, Constant Gielens
Rok vydání:	2008
Předmět:	biology Hydrogen bond Stereochemistry Organic Chemistry Active site Acetylcholinesterase chemistry.chemical_compound chemistry Nucleophilic aromatic substitution Docking (molecular) Heck reaction biology.protein Nucleophilic substitution Molecule Physical and Theoretical Chemistry
Zdroj:	European Journal of Organic Chemistry. 2008:2571-2581
ISSN:	1099-0690 1434-193X
DOI:	10.1002/ejoc.200800062
Popis:	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, 69451 Weinheim, Germany, 2008)
Databáze:	OpenAIRE
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