Design and Synthesis of Novel Dual Cholinesterase Inhibitors: In Vitro Inhibition Studies Supported with Molecular Docking

The major cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are important in the therapy of Alzheimer's disease (AD) based on the cholinergic hypothesis. As a result, in recent years, the investigation of dual cholinesterase inhibition methods has become important among scientists. In this study, novel N-(4-chlorobenzyl)-3,4-dimethoxy-N-(m-substituted)benzamide derivatives were synthesized. Then, inhibitory properties of these derivatives were examined in human AChE and BuChE in vitro and possible interactions were determined by molecular docking studies. All benzamide derivatives were exhibited dual inhibitory character and high BBB permeability. The most effective inhibitor was found as N7 for both AChE and BuChE with IC₅₀ values of 1.57 and 2.85 μM, respectively. Besides the most potent inhibitor was predicted as N7 in terms of binding energies with -12.18 kcal/mol and -9.92 kcal/mol, respectively. The reason for these results is that bromine (N7) is the bulkiest molecule among the other substituted groups. These derivatives could be exploited to develop new medications for the treatment of central nervous system-related diseases as AD by acting as dual inhibitors of AChE and BChE.