2-Quinolinone Derivatives as Dual Cholinesterase Inhibitors: Experimental and Computational Insights

Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two cholinesterases that play important roles as therapeutic targets in the cholinergic system associated with neurodegenerative diseases such as Alzheimer's disease.

The purpose of this study was to assess the in vitro inhibitory potencies of 2- quinolinone derivatives against hAChE and hBuChE and to estimate the interaction types in silico. Besides, drug-likeness characteristics (ADME) and density functional theory (DFT) calculations of the compounds were used to support the in vitro inhibition studies.

IC50-[inhibitor] graphs and Lineweaver-Burk graphs were generated. Molecular docking studies were performed by AutoDock. While ADME properties were predicted by SwissADME, DFT calculations of the compounds were made by ORCA software.

QU4 and QU6 were found to be the most effective inhibitors of AChE and BuChE with Ki values of 35.672±9.75 μM and 13.38±3.5 μM, respectively. The binding energy of QU3 against hAChE was estimated as -7.51 kcal/mol, while QU2 exhibited a binding energy of -9.11 kcal/mol against BuChE; these values are more negative than that of the reference inhibitor tacrine for both enzymes. Additionally, according to drug-likeness analysis, the derivatives except QU7 showed high blood-brain barrier permeability.

The results suggest that QU4 and QU6 derivatives may have potential for cholinesterase inhibition.

Overall, the findings of this study guide the development of more potent and selective inhibitors by appropriate structural modifications of the 2(1H)-quinolinone skeleton.