title: Rational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategy.
abstract: This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach.
authors.affiliation: Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, IRCOF, CNRS, Université et INSA de Rouen, B.P. 08, F-76131, Mont-Saint-Aignan Cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le Fur
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hagues
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Torquet
authors.forename: Cyril
authors.initials: C
authors.lastname: Papamicaël
authors.forename: Francis
authors.initials: F
authors.lastname: Marsais
authors.forename: Vincent
authors.initials: V
authors.lastname: Levacher
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D010084:Oxidation-Reduction; D048448:Phenylcarbamates / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D011804:Quinolines / Q000737:chemistry; D000068836:Rivastigmine; D013379:Substrate Specificity
chemical_list: D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D011355:Prodrugs; D011804:Quinolines; C037219:quinoline; D000110:Acetylcholinesterase; D000068836:Rivastigmine