Zhou_2026_Med.Chem.Res_35_903

A series of chalcone derivatives (8a-8v) was designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The inhibitory activities of AChE and BuChE were measured using the Ellman method. The results showed that most compounds exhibited moderate to weak inhibitory activity against both AChE and BuChE. Among them, compound 8g displayed potent AChE inhibitory activity with an IC(50) of 2.59 microM and moderate BuChE inhibitory activity with an IC(50) of 8.89 microM. The inhibitory effects of compound 8g on both enzymes surpassed those of the positive control, galantamine. Next, the antioxidant activity of these compounds was assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay, revealing that compound 8j had the strongest antioxidant activity, with an IC(50) of 65.84 microM, while the others showed weak antioxidant activity. Enzyme kinetic studies confirmed that compound 8g acts as a mixed-type inhibitor. Molecular docking indicated that compound 8g interacts with both the catalytic active site (CAS) and peripheral anion site (PAS) of AChE. Molecular dynamics (MD) simulations verified the stability of the 8g-AChE/BuChE complex. Overall, these experimental results suggest that the designed and synthesized cholinesterase inhibitor (ChEI) 8g has potential for further development.