Synthesis and biological evaluation of substituted acetamide derivatives as potential butyrylcholinestrase inhibitors

• Published in: Scientific reports Vol. 13; no. 1; p. 4877
• Main Authors: Yu, Dehong, Yang, Can, Liu, Yi, Lu, Tao, Li, Lizi, Chen, Gang, Liu, Zerong, Li, Yanfang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/154/309; 631/154/309/2420; Acetamides - pharmacology; Acetamides - therapeutic use; Acetylcholinesterase - metabolism; Age; Alzheimer Disease - drug therapy; Alzheimer's disease; Amides - therapeutic use; Bioassays; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemistry; Dementia disorders; Humanities and Social Sciences; Humans; Hydrogen bonding; Molecular Docking Simulation; Molecular dynamics; Molecular Structure; multidisciplinary; Neurodegenerative diseases; Science; Science (multidisciplinary); Structure-Activity Relationship; Therapeutic targets
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-31849-5

Alzheimer’s disease (AD) is the most common type of age-related dementia. Inhibition of butyrylcholinesterase (BChE) emerge as an effective therapeutic target for AD. A series of new substituted acetamide derivatives were designed, synthesized and evaluated for their ability to inhibit BChE. The bioassay results revealed that several compounds displayed attractive inhibition against BChE). Among them, compound 8c exhibited the highest BChE inhibition with IC 50 values of 3.94 μM. Lineweaver Burk plot indicated that 8c acted as a mixed-type BChE inhibitor. In addition, docking studies confirmed the results obtained through in vitro experiments, and showed that 8c bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. Meanwhile, its ADME parameters were approximated using in silico method. Molecular dynamics simulation studies on the complex of 8c -BChE were performed, RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds were calculated as well. These results implied that 8c could serve as appropriate lead molecule for the development of BChE inhibitor.