Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors. Issue 2 (15th January 2017)

• Record Type: Journal Article
• Authors: Basiri, Alireza; Xiao, Michelle; McCarthy, Alec; Dutta, Debashis; Byrareddy, Siddappa N.; Conda-Sheridan, Martin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 2(2017)
• Page Start: 228
• Page End: 231
• Publication Date: 2017-01-15
• Subjects: N-Benzylpiperidines -- Thiazolopyrimidinium -- AChE activity -- Molecular modeling -- π-π-Stacking interactions -- SH-SY5Y cell -- Cytotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.065
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: N -Benzylpiperidines5 and thiazolopyrimidinium salts9 derivatives, possessing multiple aromatic cores were synthesized and evaluated for AChE inhibitory activity. Compounds5h and9p displayed better inhibitory activities than galantamine having IC50 values of 0.73 and 0.83 μM, respectively. Highlights: A simple and efficient method for the synthesis of heterocycles is reported. Some compounds showed higher AChE inhibitory activity than galantamine. The most active inhibitors did not show toxicity towards human neuroblastoma cells. 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 -benzylpiperidines5 (a –h ) and thiazolopyrimidines9 (a –q ) molecules were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities. Among the newly synthesized compounds, 5h, 9h, 9j, and9p displayed higher AChE enzyme inhibitory activities than the standard drug, galantamine, with IC50 values of 0.83, 0.98, and 0.73 μM, respectively. Cytotoxicity studies of5h, 9h, 9j, 9n and9p on human neuroblastoma cells SH-SY5Y, showed no toxicity up to 40 μM concentration. Molecular docking simulations of the active compounds5h and9p 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.