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Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease

AutorSamadi, Abdelouahid ; Fuente Revenga, Mario de la; Pérez, Concepción; Iriepa, Isabel; Moraleda, Ignacio; Rodríguez-Franco, María Isabel ; Marco-Contelles, José
Palabras claveAlzheimer’s disease
ADME
Molecular modeling
In vitro blood brain barrier
6-Chloro-pyridonepezils
Dual AChE inhibitors
hAChE
hBuChE
Fecha de publicación2013
EditorElsevier
CitaciónEuropean Journal of Medicinal Chemistry 67: 64- 74 (2013)
Resumen6-Chloro-pyridonepezils are chloropyridineedonepezil 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-pyridonepezils 1-8 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-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 μM range. Particularly, 6-chloro-pyridonepezil 8 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-pyridonepezils 4, 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-pyridonepezils 1-8 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.
URIhttp://hdl.handle.net/10261/103545
DOI10.1016/j.ejmech.2013.06.021
Identificadoresdoi: 10.1016/j.ejmech.2013.06.021
issn: 0223-5234
e-issn: 1768-3254
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