Structural Optimization And Biological Activity Evaluation Of 2-ASminothiazole

Alzheimer’s disease is an important disease that threatens the health of the elderly,but the drugs to treat the disease are seriously insufficient,and new therapeutic drugs need to urgently be developed.In this paper,two new types of compounds against acetylcholinesterase as the target of Alzheimer’s disease were designed and synthesized.N-（methoxy-benzoyl）-4-phenylthiazole derivatives and N-acyl-4-（4-amino alkoxy-phenyl）-thiazole-2-amine derivatives were designed and synthesized as acetylcholinesterase inhibitors,and their structures were confirmed by ¹H NMR、¹³C NMR、HRMS.Their inhibitory activities against acetylcholinesterase（AChE）and butyrylcholinesterase（BuChE）in vitro were tested by Ellman spectrophotometry,and the cholinesterase inhibition test results showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro.Specially among of them,the bioactivity of 5k in N-（methoxy-benzoyl）-4-phenylthiazole derivatives and 10p in N-acyl-4-（4-amino alkoxy-phenyl）-thiazole-2-amine derivatives were the best,and its IC₅₀0 value were to 0.66 and 1.74μM seperatively,which were better than that of rivastigmine(IC₅₀=9.35μM)and Huperzine-A(IC₅₀=5.17μM)as reference compounds,and it had a weak inhibitory effect on butyrylcholinesterase.The results of enzyme kinetic experiments showed that the inhibitory forms of compounds 5k and 10p on AChE were competitive inhibition and mixed inhibition seperatively.In addition,potential binding modes of compounds 5k and 10p with AChE and BuChE were also studied by molecular docking.Finally,molinspiration online server was used to predict the molecular drug-like properties of all target compounds and the results showed that the predicted molecular drug-like properties of compounds 5k and 10p were within the appropriate range,showing good drug-like properties,indicating that compounds 5k and 10p have further research value.