Green Chemistry-Driven Design and Synthesis of Sulphonyl Pyrimidinones as Dual Cholinesterase Inhibitors for Alzheimer’s Disease
Sulphonyl pyrimidinones as Dual cholinesterase Inhibitor
Keywords:
AChE and BChE Inhibitory Activity, Alzheimer’s Disease, Green Chemistry Approach, Molecular Docking, Sulphonyl-Pyrimidinone DerivativesAbstract
In this study, we employed a green chemistry approach for development of novel sulphonyl Pyrimidinone derivatives as dual inhibitors of Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), enzymes implicated in the progression of Alzheimer’s disease. A series of sulphonyl pyrimidinone derivatives were synthesized by utilizing an eco-friendly method i.e. microwave-assisted synthesis, affording high yields approximately 70-85% and minimal waste. This is thoroughly characterized by using different physicochemical and spectral techniques and evaluated for dual in-vitro AChE and BuChE inhibitory activity through Ellmans method. All the synthesized compounds exhibited significant inhibitory activity against both AChE and BuChE, with IC50 values ranging from 23.00 nM to 71.66 nM and 36.00 nM to 81.00 respectively. Among the synthesized compounds 3b demonstrated strong AChE and BuChE inhibition with IC50 Values of 23.00 nM and 36.00 nM respectively, outperforming the standard drug Donepezil (AChE IC₅₀ = 37.00 nM, BuChE IC₅₀ = 46.00 nM)). Furthermore Molecular docking simulations supported that the compound 3b bound to the active sites i.e. catalytic active site (CAS) and peripheral anionic site (PAS) of both enzymes, forming π–π stacking with Tyr124 and Tyr133 in AChE, and H-bonding with Thr120 in BuChE. These findings suggest that compound containing small electron donating group (methyl) i.e. 3b could serve as promising dual-site inhibitors capable of enhancing cholinergic transmission and potentially modulating amyloid-β aggregation, making them strong candidates for further development in Alzheimer’s disease therapy. The green chemistry approach employed in this study demonstrates the potential for sustainable and environmentally friendly synthesis of Pharmaceuticals.
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