Synthesis and evaluation of new 2-oxo-1,2-dihydroquinoline-3-carboxamides as potent inhibitors against acetylcholinesterase enzyme

Alzheimer’s disease (AD), a worldwide mental disorder manifested with dementia symptoms, was used to be treated with tacrine. The latter use was terminated recently due to its hepatotoxicity. Thus, synthesis of tacrine analogues free of hepatotoxicity was attempted, a group of new 2-oxo-1,2-dihydroq...

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Bibliographic Details
Published in:Medicinal chemistry research 2022-09, Vol.31 (9), p.1448-1460
Main Authors: Alzweiri, Muhammed, Sweidan, Kamal, Saleh, Obada abu, Al-Helo, Tamam
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Alzheimer's disease
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Dementia disorders
Donepezil
Gas chromatography
Hepatotoxicity
Inorganic Chemistry
Medicinal Chemistry
Mental disorders
Neurodegenerative diseases
Original Research
Pharmacology/Toxicology
Scopolamine
Signs and symptoms
Synthesis
Tacrine
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Summary:Alzheimer’s disease (AD), a worldwide mental disorder manifested with dementia symptoms, was used to be treated with tacrine. The latter use was terminated recently due to its hepatotoxicity. Thus, synthesis of tacrine analogues free of hepatotoxicity was attempted, a group of new 2-oxo-1,2-dihydroquinoline-3-carboxamides have been synthesized and properly characterized. Their biological evaluation in inhibiting acetylcholinesterase enzyme (AChE), was evaluated by the in-house gas chromatography method. The synthesized carboxamides showed a strong potency in inhibiting AChE. Nine compounds from the group had activities higher than or close to donepezil (the positive control, IC50 ca 10 nM). For example, compound 7 depicted IC50 of 7 nM and was subsequently evaluated by the in vivo zebra fish model. Interestingly compound 7 showed better recovery from scopolamine-induced dementia than that of donepezil. Further ex vivo and in vivo models have been established recently in the lab to evaluate the safety of these compounds. Graphical abstract
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-022-02922-x