Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors

• Published in: European journal of medicinal chemistry 2015-10, Vol.103, p.361-369
• Main Authors: Mostofi, Manizheh, Mohammadi Ziarani, Ghodsi, Mahdavi, Mohammad, Moradi, Alireza, Nadri, Hamid, Emami, Saeed, Alinezhad, Heshmatollah, Foroumadi, Alireza, Shafiee, Abbas
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer's disease; Animals; Benzofuran; Benzofurans - chemistry; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Docking study; Dose-Response Relationship, Drug; Electrophorus; Molecular Structure; Pyridinium; Pyridinium Compounds - chemical synthesis; Pyridinium Compounds - chemistry; Pyridinium Compounds - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.08.061

A series of benzofuran-based chalconoids 6a–v were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6a–v showed that most compounds had significant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3-pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC50 value of 0.027 μM was as potent as standard drug donepezil. A series of benzofuran-based chalconoids bearing 3-pyridinium and 4-pyridinium moiety were synthesized as AChE inhibitors. Among them, 3-pyridinium derivative 6m with IC50 = 0.027 μM was as potent as donepezil. [Display omitted] •Benzofuran-pyridinium chalconoids 6a–v were synthesized as AChE inhibitors.•Most compounds showed anti-AChE activity at micromolar or sub-micromolar levels.•The 3-pyridinium derivative 6m exhibited superior activity (IC50 = 0.027 μM).•Compound 6m was as potent as donepezil against AChE.