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Inhibition of acetylcholinesterase (AChE) has been widely explored to develop novel molecules for management of Alzheimer's disease. In past research finding reported molecule 3-(4-(4-fluorobenzoyl)piperidin-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one displayed a spectrum of anti-Alzheimer’s properties herein, we report a library of 18 novel molecules that were rationally designed and synthesized employing known literature to mimic and explore the novel chemical space around the lead compound  6e  and donepezil. All the compounds were docked in extra-precision mode with AChE (PDB ID 4EY7) using the Glide module. Molecular dynamics (MD) simulation studies were carried out for 100 ns along with MM-PBSA studies of the trajectory frames generated post-MD simulations. Docking and MD simulation studies suggested that the synthesized compounds showed a good binding affinity with AChE. and might form stable complexes. 3-(4-(benzyl(methyl)amino)piperidin-1-yl)-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one ( 14a ; docking score: −18.59) and 1-(3,4-dimethoxybenzyl)-3-(4-(methyl(thiazol-2-ylmethyl)amino)piperidin-1-yl)pyrrolidin-2-one ( 14d ; docking score: −18.057) showed higher docking score than donepezil (docking score: −17.257) while most of the compounds had docking score &gt;-10.0. ADMET study predicted these compounds to be CNS active and most of the compounds were drug-like molecules with no HERG blockade and good to excellent oral absorption. We developed an atom-based 3 D-QSAR model with R^2 and Q^2 values of 0.9639 and 0.8779 to predict the activity of the synthesized compounds. The model predicted these compounds to be potent AChE inhibitors with IC 50  values in the lower micromolar range. Based on the  in silico  findings, we report these newly synthesized compounds 3-(4-(benzyl(methyl)amino)piperidin-1-yl)-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one  (14a)  and 7-(2,6-difluorobenzyl)-2-(4-methoxybenzyl)-2,7-diazaspiro[4.5]decan-1-one ( 20 b ) as potential AChE inhibitors. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Design, synthesis, extra-precision docking, and molecular dynamics simulation studies of pyrrolidin-2-one derivatives as potential acetylcholinesterase inhibitors