Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

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

doi:10.1016/j.bmcl.2016.11.065

Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

Bioorg Med Chem Lett. 2017 Jan 15;27(2):228-231. doi: 10.1016/j.bmcl.2016.11.065. Epub 2016 Nov 24.

Authors

Alireza Basiri¹, Michelle Xiao², Alec McCarthy³, Debashis Dutta⁴, Siddappa N Byrareddy⁴, Martin Conda-Sheridan⁵

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
² School of Engineering, Stanford University, Stanford, CA 94305, United States.
³ School of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, United States.
⁴ Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: martin.condasheridan@unmc.edu.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder affecting 35million 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 IC₅₀ values of 0.83, 0.98, and 0.73μM, respectively. Cytotoxicity studies of 5h, 9h, 9j, 9n and 9p on human neuroblastoma cells SH-SY5Y, showed no toxicity up to 40μM 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.

Keywords: AChE activity; Cytotoxicity; Molecular modeling; N-Benzylpiperidines; SH-SY5Y cell; Thiazolopyrimidinium; π-π-Stacking interactions.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Cell Line, Tumor
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Docking Simulation
Molecular Structure
Piperidones / chemical synthesis
Piperidones / chemistry
Piperidones / pharmacology*
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Piperidones
Acetylcholinesterase

Abstract

Publication types

MeSH terms

Substances

Grants and funding