Synthesis and structure-activity relationship of Huprine derivatives as human acetylcholinesterase inhibitors.
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 We have synthesized two series of Huprine analogues; in the first one, the benzene ring of the quinoline moiety has been replaced by different heterocycles or electron-withdrawing or electron-donating substituted phenyl group.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 Friedländer 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.
Ronco
Cyril
C
Equipe de Chimie Bio-Organique, COBRA-CNRS UMR 6014 & FR 3038, Mont-Saint-Aignan, France.
Sorin
Geoffroy
G
Nachon
Florian
F
Foucault
Richard
R
Jean
Ludovic
L
Romieu
Anthony
A
Renard
Pierre-Yves
PY
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase