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Design, synthesis and biological evaluation of 2,3-dihydro-5,6-dimethoxy-1H-inden-1-one and piperazinium salt hybrid derivatives as hAChE and hBuChE enzyme inhibitors.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2020 Apr 01; Vol. 191, pp. 112140. Date of Electronic Publication: 2020 Feb 13. - Publication Year :
- 2020
-
Abstract
- 2,3-Dihydro-5,6-dimethoxy-2-[4-(4-alkyl-4-methylpiperazinium-1-yl)benzylidine]-1H-inden-1-one halide salt derivatives as a novel donepezil hybrid analogs with the property of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition were designed and synthesized via N-alkylation reaction of 2,3-dihydro-5,6-dimethoxy-2-[4-(4-methylpiperazin-1-yl)benzylidene]-1H-inden-1-one with some alkyl halides. Biological tests demonstrated that most of the synthesized compounds have moderate to good inhibitory activities effect on cholinesterase enzymes. Among them, 10e showed the best profile as a selected compound for inhibition of hAChE (IC50 = 0.32) and hBuChE (IC50 = 0.43 μM) enzymes. Kinetic analysis and molecular docking led to a better understanding of this compound. Kinetic studies disclosed that 10e inhibited acetylcholinesterase in mixed-type and butyrylcholinesterase in non-competitive type. The toxicity results showed that 10e is less toxic than donepezil and has better inhibitory activity against hBuChE when compared to donepezil or Galantamine. Other performed experiments revealed that 10e has an anti-β amyloid effect which is capable of reducing ROS, LDH and MDA also possing positive effect on TAC. On the other hand, it has shown a good anti-inflammation effect.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Acetylcholinesterase genetics
Algorithms
Butyrylcholinesterase genetics
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Dose-Response Relationship, Drug
Humans
Indenes chemical synthesis
Indenes chemistry
Molecular Docking Simulation
Molecular Structure
Piperazines chemical synthesis
Piperazines chemistry
Salts chemical synthesis
Salts chemistry
Salts pharmacology
Structure-Activity Relationship
Acetylcholinesterase metabolism
Butyrylcholinesterase metabolism
Cholinesterase Inhibitors pharmacology
Drug Design
Indenes pharmacology
Piperazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 191
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32088494
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112140