Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors are used to increase acetylcholine levels in current symptomatic treatments for Alzheimer's disease (AD), which is still the most common neurodegenerative illness. Through the synthesis and thorough assessment of a novel series of Imidazo-pyrazinone derivatives (8a-8l), this study sought to identify and create highly effective cholinesterase inhibitors. Using donepezil as the standard reference medication, the produced compounds were tested in vitro for their inhibitory activity against both AChE and BuChE (AChE IC50 (μM) 2.16 ± 0.12, BuChE IC50 (μM) 4.50 ± 0.11). The findings showed that most of the recently created derivatives had better inhibitory activity than the reference medication. Compound 8h was the most effective dual inhibitor in the series, outperforming Donepezil with an AChE IC50 of 1.22 ± 0.30 and a BuChE of 3.75 ± 1.20. Derivatives with electron-withdrawing groups, such as the fluoro substituent, particularly at the meta-position, and these strengthens interactions around the enzyme's active site, demonstrated the greatest levels of inhibition, according to the structure-activity relationship (SAR) studies. The ortho-position hydroxyl (-OH) phenolic group in compound 8h was also found to be an important structural feature that increased potency by encouraging helpful hydrogen bonding with catalytic residues. In order to investigate the binding mode, reliability, and electronic characteristics of the most active compounds, molecular docking and Density Functional Theory (DFT) calculations have been carried out in addition to the studies. The results of the experiment were supported by the docking analysis, which verified the advantageous penetration of compound 8h through the active site. Additionally, the most promising candidates' acceptable pharmacokinetic profiles and drug-likeness were predicted through ADME (Absorption, Distribution, Metabolism, and Excretion) evaluation. To sum up, compound 8h, a novel imidazo-pyrazinone derivative, is a potent dual AChE and BuChE inhibitor that deserves more in vivo investigation as a potential lead compound for Alzheimer's disease treatment.
Alharbi et al. (2026) studied this question.