Synthesis and molecular dynamic simulation studies of novel N-(1-benzylpiperidin-4-yl) quinoline-4-carboxamides as potential acetylcholinesterase inhibitors

Abstract A new series of N-(1-benzylpiperidin-4-yl) quinoline-4-carboxamide derivatives was designed and synthesized as potential acetylcholinesterase inhibitors. The compounds were characterized by nuclear magnetic resonance, infrared and mass spectrometry. In the amidation reaction in addition of target compounds 5a-5 h, a bis-N-acylurea were also obtained especially when we added more carbonyldiimidazole (CDI) for the completion of the reaction. Although docking study of these compounds predicted that they will inhibit acetylcholinesterase (AChE) protein strongly and more than the reference drugs, the in vitro evaluation of the quinolines 5a-5 h revealed that most of them had moderate activity toward AChE. The results showed that there is a correlation between anticholinesterase inhibitory potency and docking energy of compounds. Among these compounds, 5f with the lowest docking energy, exhibited the most anticholinesterase inhibitory potency. Molecular dynamics simulation and molecular docking studies of compound 5f into the binding site of acetylcholinesterase exhibited the probable interactions of 5f with the binding site of acetylcholinesterase.