Li_2025_Bioorg.Med.Chem_129_118296

The purpose of this study is to develop more effective therapeutic agents to slow or prevent Alzheimer's progression. A lead compound ZINC4372573 was identified by using molecular docking and molecular dynamics simulation techniques. A series of novel vanillin derivatives were designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The in vitro assay results show that compound 4c exhibits the most potent inhibitory activity against both AChE and BuChE, with IC(50) values of 0.18 microM and 7.61 microM, respectively. This performance is superior to the positive control drug galantamine (AChE IC(50) = 3.65 microM; BuChE IC(50) = 15.29 microM). Molecular docking study reveals that the good activity of 4c may be attributed to the preferable docking mode, robust intermolecular interactions (including Pi-Pi stacking and hydrogen bonding), and the superior binding properties of the indole ring. Cytotoxicity test for compound 4c was further performed by CCK-8 method, with results indicating a favorable safety profile. In addition, antioxidant test for 4c reveals its notable antioxidant activity. These findings suggest that 4c holds potential as a promising dual AChE/BuChE inhibitor for the development of novel therapeutic agents targeting Alzheimer's disease. Subsequent investigations will prioritize comprehensive evaluation of in vivo therapeutic efficacy and pharmacokinetic characterization, thereby facilitating translational development toward clinical applications.