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

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

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

Conclusion: 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.