Blood-brain barrier permeable benzylpiperidin-4-yl-linked benzylamino benzamides as dual cholinesterase inhibitors

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 mu M, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed-type mode of inhibition for AChE and BChE with k(i) values of 0.14 and 0.46 mu M, respectively. The derivative 8c1 crosses the blood-brain barrier as indicated by the P-e value of 14.34 x 10(-6)cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self-aggregation of amyloid-beta. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.

Automated summary

This study investigated the benzyl piperidinyl-linked benzyl aminobenzamide as a dual cholinesterase inhibitor. The compound showed inhibition of acetylcholinesterase and butyrylcholinesterase and crossed the blood-brain barrier. It also inhibited the self-aggregation of amyloid-beta. These findings suggest the potential of benzamide 8c1 for further investigation in preclinical models of Alzheimer's disease.