Alireza Basiri1, Michelle Xiao2, Alec McCarthy3, Debashis Dutta4, Siddappa N Byrareddy4, Martin Conda-Sheridan5. 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.
Alzheimer's disease (n class="Disease">AD) is a neurodegenerative disorder affecting 35million people worldwide. A common strategy to improve the well-being of ADpatients 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 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 humanneuroblastoma 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.
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