Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors

Abstract

Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corroborated well with in vitro activities and kinetic studies.