Design, Green Synthesis, DFT Analysis, and Docking Study of Aryl Pyrano-Bis-Coumarin Derivatives as Acetyl Cholinesterase Inhibitors

Abstract

Abstract This study focuses on the design, green synthesis, and biological evaluation of a series of novel pyrano-bis-coumarin analogs as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. A new saccharin-based ionic liquid, tris(2-hydroxyethyl)ammonium 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetate, was efficiently designed and synthesized and employed as a novel green catalyst. This ionic liquid facilitated the synthesis of various aryl bis-coumarin derivatives (5a–j) under solvent-free conditions using microwave irradiation. The structures of the ionic liquid and all synthesized compounds were confirmed by NMR, IR, and elemental analyses. The target compounds were evaluated for their inhibitory activity against AChE and BChE enzymes. Preliminary biological results indicated that all synthesized analogs exhibited inhibitory activity against both enzymes compared with the standard drug donepezil. Among them, the nitro-substituted analog 5b showed the highest potency against AChE with IC50 value of 2.55 µM. Density functional theory (DFT) calculations and molecular docking studies were performed to elucidate the binding interactions between the most active compound and the enzyme active site. Compound 5b demonstrated a calculated binding energy of −11.84 kcal/mol with AChE, with significant cation–π interactions observed. Overall, this study highlights the significance of green synthetic strategies combined with molecular design in identifying promising aryl bis-coumarin scaffolds as potential leads for the development of new acetylcholinesterase inhibitors for the treatment of neurodegenerative disorders such as Alzheimer’s disease. Graphical AbstractChemical synthesis of coumarin derivatives in two steps, using a complex catalyst, and a 3D ball-and-stick molecular model.