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, Mario De La Fuente Revenga, Concepción Pérez, Isabel Iriepa, Ignacio Moraleda, María Isabel Rodríguez-Franco, José Marco-Contelles

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

6-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.

Original languageEnglish
Pages (from-to)64-74
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume67
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • 6-Chloro-pyridonepezils
  • ADME
  • Alzheimer's disease
  • Dual AChE inhibitors
  • In vitro blood brain barrier
  • Molecular modeling
  • hAChE
  • hBuChE

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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