Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase

[Display omitted] •Carboxamide/propanamide derivatives of phenylpyridazine/biphenyl were synthesized.•Most of the carboxamide derivatives were selective for AChE.•The most active compounds inhibit AChE at submicromolar/micromolar concentration.•Kinetic study showed that most active compound was mixe...

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Bibliographic Details
Published in:Bioorganic chemistry 2018-09, Vol.79, p.235-249
Main Authors: Kilic, Burcu, Gulcan, Hayrettin O., Aksakal, Fatma, Ercetin, Tugba, Oruklu, Nihan, Umit Bagriacik, E., Dogruer, Deniz S.
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Acetylcholinesterase inhibitory activity
Alzheimer’s disease
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Butyrylcholinesterase - metabolism
Butyrylcholinesteraseinhibitory activity
Cell Survival - drug effects
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Dose-Response Relationship, Drug
Drug Design
Electrophorus
Horses
Mice
Molecular docking
Molecular Docking Simulation
Molecular Structure
NIH 3T3 Cells
Pyridazine
Pyridazines - chemistry
Pyridazines - pharmacology
Structure-Activity Relationship
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Summary:[Display omitted] •Carboxamide/propanamide derivatives of phenylpyridazine/biphenyl were synthesized.•Most of the carboxamide derivatives were selective for AChE.•The most active compounds inhibit AChE at submicromolar/micromolar concentration.•Kinetic study showed that most active compound was mixed type inhibitor for AChE. A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2018.05.006