Mohammadi-Farani_2024_Results.Chem_7_101273

The cholinergic hypothesis is one of the basic approaches for designing and discovering novel anti-Alzheimer drugs. Application of the pharmacophore of well-known drugs like donepezil helps us achieve new molecules. In the current project, a new series of benzamide derivatives (6a6l) were designed and synthesized. Spectroscopic techniques (NMR, IR, MS) were utilized for characterization. Subsequently, Ellmans protocol was carried out for acetylcholinesterase assay and the obtained results were compared to donepezil (IC50 = 0.6 0.05 M). Compound 6b which bears a chlorine atom at position meta of the phenyl ring was the most potent derivative in this series (IC50 = 0.14 0.03 nM) and exhibited higher activity than donepezil. In addition, molecular docking was performed to explore the binding mode and related interactions. The in silico results demonstrated that compound 6b binds to the active site of the AChE through a hydrogen bond with Trp279. This compound could be suggested as a potential lead compound and more experimental and in vivo tests are needed to prove its eligibility as a drug candidate.