Synthesis And Biological Activity Evaluation Of New Pyrazine Derivatives

Alzheimer’s disease was a chronic neurodegenerative disease that seriously affects the healthy life of the elderly.The drugs currently used for treatment cannot be cured fundamentally,and the development and synthesis of new drugs has become an inevitable trend.In this paper,a series of pyrazine derivatives have been designed and synthesized for the treatment of acetylcholinesterase,the target of the disease.Pyrazinone derivatives and pyrazine-2-amide derivatives were designed and synthesized as acetylcholinesterase inhibitors,and their structures were confirmed by ¹H NMR,¹³CNMR and MS spectroscopy,Their inhibitory activities against acetylcholinesterase（AC h E）and butyrylcholinesterase（BuChE）in vitro were tested by Ellman spectrophotometry,The results of the cholinesterase inhibition test showed that compound 6c among pyrazinone derivatives and compound 8d among pyrazine-2-amide derivatives had the highest inhibitory activity against AC h E,and its IC₅₀ value were to 0.82 and 0.83μM,respectively,which were better than that of Huperzine A(IC₅₀=5.28μM)as reference compounds;and it had a weak inhibitory effect on butyrylcholinesterase,showing excellent specificity for AC h E.Compound6f has the strongest inhibitory activity on Bu C h E,with IC₅₀ reaching 0.92μM,indicating its selectivity for Bu C h E.At the same time,the enzymatic kinetic analysis of compounds 6c and8d,which have the best AChE inhibitory activity,was carried out.The experimental results showed that the inhibitory modes of co mpounds 6c and 8d to AChE were mixed inhibition.Then the interaction of compounds 6c 8d and 6f with AChE and BuChE was further studied by molecular docking software.In addition,the Molinspiration online server was used to predict the molecular drug properties of all synthesized target compounds.The prediction results showed that the predicted values of compounds 6c 8d and 6f were within a reasonable range,which complied with the molecular drug properties rules,Has the potential for further development.