Synthesis, in silico study, and biological evaluation of cyclosulfamide derivatives as new anticholinesterase inhibitors

Abstract

After the great spread of Alzheimer's disease (AD) in the past few years, many researchers directed their work toward developing an effective treatment for this disease and to discovering very advanced drugs. Cyclosulfamides are considered as versatile pharmacophores in the construction of new molecules with excellent activities. Therefore, a series of cyclosulfamide have been synthesized and evaluated as anti-Alzheimer agents through in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition. Most of tested compounds showed an average inhibitory activity against two targeted enzymes compared with the reference ligand. Specifically, 10a showed the best inhibition of AChE enzyme with an IC50 = 45.30±0.88 µM; while 4a exhibited the most potent BuChE enzyme inhibition with an IC50 = 52.87±3.73 µM.Further, we were able to determine a feasible binding mode for cyclosulfamide derivatives owing to molecular docking studies, which offered prospective evidence to identify significant interactions between the active site of AChE and the synthesized ligands.Following the encouraging findings of the molecular docking investigation, the complex AChE-10a was put through a 100 ns Desmond of Schrodinger simulation of molecular dynamics (MD), during which the receptor-ligand combination showed significant stability after 10 ns of MD simulation.