Abstract
In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
Keywords:
Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Molecular docking; Quinoline; Triazolopyrimidine.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Amyloid beta-Peptides / chemistry
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Animals
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Antioxidants / chemical synthesis*
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Antioxidants / pharmacokinetics
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Antioxidants / pharmacology*
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Antioxidants / therapeutic use
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Butyrylcholinesterase / chemistry
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Butyrylcholinesterase / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Chemistry Techniques, Synthetic
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / pharmacokinetics
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Cholinesterase Inhibitors / pharmacology*
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Cholinesterase Inhibitors / therapeutic use
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Drug Evaluation, Preclinical
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Humans
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Kinetics
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Molecular Docking Simulation
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Peptide Fragments / chemistry
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Protein Aggregates / drug effects
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Protein Conformation
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
Substances
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Amyloid beta-Peptides
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Antioxidants
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Cholinesterase Inhibitors
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Peptide Fragments
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Protein Aggregates
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Pyrimidines
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amyloid beta-protein (1-42)
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Acetylcholinesterase
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Butyrylcholinesterase