Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: Synthesis, biological assessment, and molecular modeling

Abdelouahid Samadi, Martín Estrada, Concepción Pérez, María Isabel Rodríguez-Franco, Isabel Iriepa, Ignacio Moraleda, Mourad Chioua, José Marco-Contelles

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

The synthesis, biological assessment and molecular modeling of new pyridonepezils 1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6- chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4- yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1- benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC50 (hAChE) = 9.4 ± 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil 7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils 1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.

Original languageEnglish
Pages (from-to)296-301
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume57
DOIs
Publication statusPublished - Nov 2012
Externally publishedYes

Keywords

  • ADME
  • Alzheimer's disease
  • Dual AChE inhibitors
  • In vitro blood brain barrier
  • Molecular modeling
  • Pyridonepezils
  • hAChE
  • hBuChE

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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