2-Substituted-5-(4-substitutedsulfonylamido)benzoxazoles as potent cholinesterase inhibitors: Synthesis, in vitro, molecular docking, molecular dynamics simulation, and DFT studies

Alzheimer's disease (AD), the most worrisome neurological condition in the world, is one of the primary causes of dementia and is characterized by cognitive and memory loss. This disease is multifactorial, and there is currently no cure, although treatments based on the cholinergic hypothesis have been successful in relieving symptoms. This study examined the inhibitory effects of 11 compounds with a sulfonamide group at position 5 of the benzoxazole ring system on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Two of these 11 compounds are original, and FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry were used to characterize their structures. The compounds showed significantly greater biological activity as inhibitors of both AChE and BChE than the reference drug, donepezil. In particular, 2a showed the highest activity against AChE with a Ki value of 7.45 ± 2.79 nM, and 1b showed the highest activity against BChE with a Ki value of 3.37 ± 0.68 nM. Furthermore, a molecular docking study was performed to investigate the interaction modes of the active compounds with the active sites of the crystal structures of AChE and BChE. Hydrogen bond and π interactions were observed in the protein–ligand interactions. The stabilities of the complexes obtained from docking were assessed using a molecular dynamics (MD) simulation. The MD simulation revealed that the complexes remained stable throughout. Density functional theory (DFT) analysis was also conducted to determine the compounds' most stable conformers and investigate their chemical stability and reactivity. © 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.