期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 13, 页码 4523-4536出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.05.005
关键词
Huprines; AChE inhibitors; Heterodimers; Alzheimer's disease; Friedlander reaction
资金
- MRES ('Ministere de l'Enseignement Superieur et de la Recherche')
- FRM('Fondation pour la Recherche Medicale')
- IUF ('Institut Universitaire de France')
- Region Haute Normandie, CRUNCh program [CPER 2007-2013]
New series of Huprine (12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolines) derivatives have been synthesized and their inhibiting activities toward recombinant human acetylcholinesterase (rh-AChE) are reported. We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group. The second one has been designed in order to evaluate the influence of modification at position 12 where different short linkers have been introduced on the Huprine X, Y skeletons. All these molecules have been prepared from ethyl- or methyl-bicyclo[3.3.1]non-6-en-3-one via Friedlander reaction involving selected o-aminocyano aromatic compounds. The synthesis of two heterodimers based on these Huprines has been also reported. Activities from moderate to same range than the most active Huprines X and Y taken as references have been obtained, the most potent analogue being about three times less active than parent Huprines X and Y. Topologic data have been inferred from molecular dockings and variations of activity between the different linkers suggest future structural modifications for activity improvement. (C) 2009 Elsevier Ltd. All rights reserved.
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