Short communication Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease Abdelouahid Samadi a, * , Mario de la Fuente Revenga b , Concepción Pérez b , Isabel Iriepa c , Ignacio Moraleda c , María Isabel Rodríguez-Franco b , José Marco-Contelles a, * a Laboratorio de Química Médica, Instituto de Química Orgánica General (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain b Instituto de Química Médica (IQM e CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain c Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817 Alcalá de Henares, Spain article info Article history: Received 17 April 2013 Received in revised form 31 May 2013 Accepted 4 June 2013 Available online 25 June 2013 Keywords: hAChE hBuChE Dual AChE inhibitors 6-Chloro-pyridonepezils In vitro blood brain barrier Molecular modeling ADME Alzheimer’s disease abstract 6-Chloro-pyridonepezils are chloropyridineedonepezil hybrids designed by combining the N-benzylpi- peridine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1e8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine- 3,5-dicarbonitrile (14)] with suitable 2-(1-benzylpiperidin-4-yl)alkylamines (9e12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC 50 ¼ 0.47  0.08 mM). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC 50 in the 0.013e0.054 mM range. Particularly, 6-chloro-pyr- idonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equi- potent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6e8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at pe- ripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1e8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer’s therapy. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Alzheimer’s disease (AD) is the most prevalent neurodegener- ative disorder [1]. AD is characterized by the gradual development of forgetfulness, progressing to disturbances in language, disori- entation, and mutism. The symptomatic course of the disease is generally five or more years of stepwise decline in memory and attention span [2]. Typical pathological hallmarks are extracellular senile plaques, consisting principally of amyloid-b (Ab), and intra- cellular neurofibrillary tangles, which are composed of phosphor- ylated tau protein. Moreover, the basal nucleus of Meynert undergoes profound neuron loss, the neocortex exhibits a loss of cholinergic fibers and receptors, and a decrease of both choline acetyltransferase and acetylcholinesterase (AChE) enzyme activity [2,3]. Since the symptoms of AD were associated with an altered cholinergic function, research has been focused on the basal fore- brain cholinergic system [3]. As a result, the cholinergic hypothesis was developed, which postulated that a loss of cholinergic function in the central nervous system contributed significantly to the cognitive decline associated with advanced age and AD [4]. Thus, drugs capable of inhibiting AChE might potentiate central cholin- ergic function, therefore improving cognition and perhaps even some of the behavioral problems experienced by AD patients [5]. AChE inhibitors (AChEI) may inhibit AChE via a competitive mechanism, by interacting with the catalytic active site (CAS) of the enzyme, via a non-competitive mechanism, by binding with the peripheral anionic site (PAS), or via both mechanisms, by exerting a dual binding AChE inhibition. For a while the treatment with AChEI was reported to produce only symptomatic improvement, having no effect in the course of the disease [6]. However, other studies * Corresponding authors. Fax: þ34 91 5644853. E-mail addresses: samadi@iqog.csic.es, asamadi1972@gmail.com, samadi72@ yahoo.com (A. Samadi), iqoc21@iqog.csic.es (J. Marco-Contelles). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.06.021 European Journal of Medicinal Chemistry 67 (2013) 64e74