PAPER www.rsc.org/obc | Organic & Biomolecular Chemistry Rational design of central selective acetylcholinesterase inhibitors by means of a “bio-oxidisable prodrug” strategy† Pierre Bohn, a,b Nicolas Le Fur, a Guillaume Hagues, b Jean Costentin, b Nicolas Torquet, b Cyril Papamica¨ el, a Francis Marsais a and Vincent Levacher* a Received 13th February 2009, Accepted 8th April 2009 First published as an Advance Article on the web 18th May 2009 DOI: 10.1039/b903041g 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 (IC 50 > 10 6 nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC 50 ranging from 6 mM 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. Introduction Alzheimer’s disease (AD), the most common form of dementia affecting elderly people, is a complex irreversible neurological affection clinically characterized by a progressive loss of memory and impairment of cognitive functions. While 1% to 3% of the population aged under 65 years are affected, more than 30% of people over 85 years of age are affected by this neurodegenerative disorder. Given the ageing of the population, AD is becoming one of the most important healthcare problems in developed countries. 1 Although the origin of AD is still under debate, amyloid plaques and neurofibrillary tangles observed in post- mortem brain studies in neurocortex and hippocampus regions are held responsible for the devastating clinical effects of the disease. 2 Another important and significant aspect of neurodegeneration in the brain of AD patients is the loss of the basal forebrain cholin- ergic system, thought to play a crucial role in producing cognitive impairments and memory deficiency. Therefore, enhancement of the central cholinergic transmission has been considered as a promising approach for the symptomatic treatment of AD. Among the diverse strategies explored, 3 acetylcholinesterase (AChE) in- hibitors have been extensively studied. This approach has provided a Laboratoire de Chimie Organique Fine et H´ et´ erocyclique, UMR 6014, IRCOF, CNRS, Universit´ e et INSA de Rouen, B.P. 08, F-76131, Mont- Saint-Aignan Cedex, France. E-mail: vincent.levacher@insa-rouen.fr; Fax: +33(0)235522962 b Laboratoire de Neuropharmacologie Exp´ erimentale associ´ e au CNRS (FRE-2735). Facult´ e de M´ edecine et de pharmacie, Universit´ e de Rouen, F-76000, France †Electronic supplementary information (ESI) available: Analytical data and purification conditions of 11a–g, 1a–g, 2a–g, 1 H and 13 C NMR spectra of 3, 4, 6–9, 10b–f, 11a–f, 1a–d,f, 2a–f, preparation of AChE and detailed procedure for AChE inhibition assay. See DOI: 10.1039/b903041g the sole clinically effective method for a palliative treatment of mild to moderate AD. 4 Over the past decade, several AChE inhibitors such as tacrine, 5 donepezil, 6 rivastigmine 7 and more recently galanthamine 8 have been launched on the market. Although all AChE inhibitors employed in AD therapy exhibit a preferential action in the central nervous system (CNS), the manifestation of peripheral activity in the course of the treatment causes serious adverse effects on peripheral organs and seriously limits the therapeutic potential of these cholinesterase inhibitors. Therefore, the design of central selective AChE inhibitors free from adverse peripheral effects remains a major challenging therapeutic goal. The strategy disclosed in this work brings into play a “bio- oxidisable prodrug” which, after having crossed the blood-brain barrier (BBB), is expected to be converted to the parent drug in the CNS, via a redox-activation process. 9 Our aim is to report herein the design, synthesis and preliminary in vitro biological evaluation of these new potential central selective AChE inhibitors. Results and discussion “Bio-oxidisable prodrug” design of cyclic rivastigmine analogues The design of this “bio-oxidisable prodrug” approach is closely connected with the action mechanism of AChE inhibitors. Whereas donepezil and galanthamine are competitive inhibitors, rivastigmine displays a pseudo-irreversible inhibition involving the carbamylation of the serine hydroxyl group located at the “esterasic site” of the enzyme. Both classes of these inhibitors share in common a tertiary amine which is known to play a central role in the mechanism of AChE inhibition. At physiological pH, the protonation of this amine results in the formation of a positive 2612 | Org. Biomol. Chem., 2009, 7, 2612–2618 This journal is © The Royal Society of Chemistry 2009 Downloaded by INSA Rouen on 28 September 2012 Published on 18 May 2009 on http://pubs.rsc.org | doi:10.1039/B903041G View Online / Journal Homepage / Table of Contents for this issue