Issue 12, 2009

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 > 106 nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 μM 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.

Graphical abstract: Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy

Supplementary files

Article information

Article type
Paper
Submitted
13 Feb 2009
Accepted
08 Apr 2009
First published
18 May 2009

Org. Biomol. Chem., 2009,7, 2612-2618

Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy

P. Bohn, N. Le Fur, G. Hagues, J. Costentin, N. Torquet, C. Papamicaël, F. Marsais and V. Levacher, Org. Biomol. Chem., 2009, 7, 2612 DOI: 10.1039/B903041G

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