Shakoor_2026_Future.Med.Chem__1

AIMS: The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). METHODS: Ten benzimidazole Schiff bases were synthesized and characterized by spectroscopic techniques. These compounds were assessed for in vitro AChE and BuChE inhibitory activities. Density functional theory (DFT) analysis was carried out to know the electronic properties, while molecular docking studies were performed to expose protein ligand interactions. RESULTS: In the series, compounds (2c, 2f, 2h, 2a, and 2b) displayed potent inhibition against AChE and BuChE comparable to the standard galantamine. DFT study showed that compounds having higher electrophilicity (omega), lower hardness (), higher softness (sigma), and lower energy gap (sigma) increase the inhibitory activity. In addition, electron donating groups at meta position of the benzene improved the potency, while docking studies confirmed favorable binding interactions with the active site of the enzymes. DISCUSSION: These consequences show that both geometric and electronic properties have a vital role in determining the cholinesterase inhibition. These derivatives facilitate multiple interactions within the enzyme active site, supporting its potential as biologically relevant nucleus. CONCLUSION: The experimental and computational findings provide valuable insights for the optimization and rational design of new therapeutic agents for Alzheimer's disease.