Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

Alireza Basiri, Michelle Xiao, Alec McCarthy, Debashis Dutta, Siddappa N. Byrareddy, Martin Conda-Sheridan

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder affecting 35 million people worldwide. A common strategy to improve the well-being of AD patients consists on the inhibition of acetylcholinesterase with the concomitant increase of the neurotransmitter acetylcholine at cholinergic synapses. Two series of unreported N-benzylpiperidines 5(a–h) and thiazolopyrimidines 9(a–q) molecules were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities. Among the newly synthesized compounds, 5h, 9h, 9j, and 9p displayed higher AChE enzyme inhibitory activities than the standard drug, galantamine, with IC50values of 0.83, 0.98, and 0.73 μM, respectively. Cytotoxicity studies of 5h, 9h, 9j, 9n and 9p on human neuroblastoma cells SH-SY5Y, showed no toxicity up to 40 μM concentration. Molecular docking simulations of the active compounds 5h and 9p disclosed the crucial role of π-π-stacking in their binding interaction to the active site AChE enzyme. The presented compounds have potential as AChE inhibitors and potential AD drugs.

Original languageEnglish (US)
Pages (from-to)228-231
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number2
DOIs
StatePublished - 2017

Keywords

  • AChE activity
  • Cytotoxicity
  • Molecular modeling
  • N-Benzylpiperidines
  • SH-SY5Y cell
  • Thiazolopyrimidinium
  • π-π-Stacking interactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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