title: Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease.
abstract: 6-Chloro-pyridonepezils are chloropyridine-donepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils1-8 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 (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 ± 0.08 μM). 6-Chloro-pyridonepezils4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 μM range. Particularly, 6-chloro-pyridonepezil8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils1-8 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.
authors.affiliation: Laboratorio de Química Médica, Instituto de Química Orgánica General (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: samadi@iqog.csic.es.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Mario
authors.initials: M
authors.lastname: de la Fuente Revenga
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C587476:6-chloro-pyridonepezil; D002800:Cholinesterase Inhibitors; D011728:Pyridones; D000110:Acetylcholinesterase
keywords: 6-Chloro-pyridonepezils; ADME; Alzheimer's disease; Dual AChE inhibitors; In vitro blood brain barrier; Molecular modeling; hAChE; hBuChE