LAUSR

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder involving various pathological events. The existing options for managing the disease utterly rely on cholinesterase (ChE) inhibitors. In recent years, the dual inhibition of ChEs as a potential AD therapeutics has substantially attracted the attention of medicinal chemists. Recently, we reported benzyl piperidinyl‐linked methoxy‐naphthamides as dual ChE inhibitors. Herein, we investigated the peripheral anionic binding site‐binding methoxy‐naphthamide fragment that yielded benzyl piperidinyl‐linked benzyl aminobenzamide as another class of dual ChE inhibitors. The 3,5‐dimethoxy benzyl aminobenzamide, 8c1, exhibits inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with half‐maximal inhibitory concentration values of 0.61 and 2.04 µM, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed‐type mode of inhibition for AChE and BChE with ki values of 0.14 and 0.46 µM, respectively. The derivative 8c1 crosses the blood–brain barrier as indicated by the Pe value of 14.34 × 10−6cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self‐aggregation of amyloid‐β. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.