Design, synthesis and assay of 2-(4-phenylpiperazin-1-yl)pyrimidine-5- carboxamide derivatives as acetylcholinesterase inhibitors

A series of 2-(4-phenylpiperazin-1-yl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized for the treatment of Alzheimer’s disease (AD). Their bioactivities were evaluated by the Ellman’s method, and the results showed that most of synthesiz...

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Bibliographic Details
Published in:Medicinal chemistry research 2022-11, Vol.31 (11), p.1901-1915
Main Authors: Wei, Ben-Ben, Han, Chuang, Shang, Pan-Pan, Guo, Xin-Yuan, Bai, Li-Gai, Ma, Zheng-Yue
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Alzheimer's disease
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Drug development
Inhibitors
Inorganic Chemistry
Lead compounds
Medicinal Chemistry
Molecular docking
Neurodegenerative diseases
Original Research
Pharmacology/Toxicology
Synthesis
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Summary:A series of 2-(4-phenylpiperazin-1-yl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized for the treatment of Alzheimer’s disease (AD). Their bioactivities were evaluated by the Ellman’s method, and the results showed that most of synthesized compounds displayed moderate acetylcholinesterase inhibitory activities in vitro. Among them, compound 6g exhibited the most potent inhibitory activity against AChE with IC 50 of 0.90 μM, and poor inhibitory activity against butyrylcholinesterase (BuChE) with IC 50 of 7.53 μM, which indicated that compound 6g was a selective AChE inhibitor, and compound 6g as a selective AChE inhibitor was confirmed by the molecular docking studies of compound 6g with AChE and BuChE. Furthermore, the mechanism of inhibition of compound 6g against AChE was analyzed by the kinetic study, and the result indicated that compound 6g was the mixed-type inhibitor of competitive inhibition and non-competitive inhibition. All the above showed that compound 6g could be considered as a lead compound for the development of AD drugs. Graphical abstract
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-022-02949-0