Synthesis, characterization, and biological evaluation of some new molecules containing piperidin-1-yl-phenyl-acetamide moiety

Novel multifunctional medication candidates are needed to treat Alzheimer’s disease (AD), a neurodegenerative illness with few treatments. A nitrogen-containing heterocycle, piperidine, is a popular medicinal chemistry scaffold with broad therapeutic potential. We synthesized a series of novel piperidin-1-yl-phenyl-acetamide derivatives (AS-1 to AS-5) by reacting piperidine with 4-chloroaniline and characterizing them by IR, 1 H NMR, 13 C NMR, and mass spectrometry. All compounds meet Lipinski’s rule of five for drug-likeness and oral bioavailability. AutoDockVina molecular docking demonstrated that compounds AS-5 and AS-2 bind acetylcholinesterase (AChE) with affinities comparable to or higher than donepezil, suggesting they may inhibit AChE. AS-5 was the most potent free radical scavenger in DPPH and FRAP studies. Further behavioral evaluation utilizing Y-maze and Morris water maze tests showed that AS-5 was more effective against Alzheimer’s than AS-1. Piperidin-1-yl-phenyl-acetamide derivatives, particularly the 2,5-dimethyl-substituted counterpart (AS-5), have multifunctional properties due to acetylcholinesterase inhibition and antioxidant activity. These findings suggest AS-5 as a lead chemical for optimizing and developing Alzheimer’s disease treatments. The piperidin-1-yl-phenyl-acetamide derivative (AS-5)’s significant acetylcholinesterase inhibition, robust antioxidant action, and in vivo cognitive enhancement comparable to Donepezil make it important. Structure–activity relationship insight highlights the 2,5-dimethyl substitution as a significant driver of increased anti-Alzheimer action, providing a target for next-generation drug design.