title: Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors.
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 IC50values 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Alireza
authors.initials: A
authors.lastname: Basiri
authors.affiliation: School of Engineering, Stanford University, Stanford, CA 94305, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Xiao
authors.affiliation: School of Biological Systems Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, United States.
authors.forename: Alec
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Debashis
authors.initials: D
authors.lastname: Dutta
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Siddappa N
authors.initials: SN
authors.lastname: Byrareddy
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: martin.condasheridan@unmc.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010881:Piperidones; D000110:Acetylcholinesterase
keywords: AChE activity; Cytotoxicity; Molecular modeling; N-Benzylpiperidines; SH-SY5Y cell; Thiazolopyrimidinium; π-π-Stacking interactions