Structural Optimization And Biological Activity Test Of 4-arylthiazole-2-amine

Alzheimer’s Disease（AD）is a neurodegenerative disease characterized by memory loss,cognitive deficits,and behavioral disorders.Currently,acetylcholinesterase inhibitors（AChEIs）are the most widely used drugs for the treatment of AD in the clinic.However,the existing AChEIs can only alleviate the symptoms of some AD patients,and could not meet the clinical needs.Therefore,finding new and efficient,low-toxic AChEIs are still the direction of scientific research workers.We put cholinergic hypothesis as the guiding principle and took the reported compound N-（4-（4-methoxy-phenyl）thiazol-2-yl）-3-（pyrrolidin-1-yl）propionamide which had a good inhibitory activity as a lead compound,the new 4-arylthiazole-2-amine derivatives were synthesized from 4-methoxyacetophenone and 2-acetylpyridine,respectively.Their in vitro inhibitory activities against acetylcholinesterase were also tested by Ellman spectrophotometry.The chemical structures of the 4-arylthiazole-2-amine derivatives prepared herein were confirmed by ¹HNMR,MS,IR and other spectroscopy techniques.Their in vitro acetylcholinesterase inhibitory activity test results show ed that most of the compounds of 4-phenylthiazole-2-amine derivatives had certain in vitro acetylcholinesterase inhibitory activity,and the IC₅₀ of compound 5g was 5.84μmol/L,the activity was higher than that of reference compound,Rivastigmine,and had almost no inhibitory effect on butyrylcholinesterase;the 4-pyridylthiazol-2-amine derivatives also had certain in vitro acetylcholinesterase inhibitory activity,and the IC₅₀ of compound 11b was5.72μmol/L,the activity was also higher than that of reference compound,Rivastigmine,at the same time,it had almost no inhibitory effect on butyrylcholinesterase and had good specificity.In addition,the compounds with better in vitro acetylcholinesterase inhibitory activity of 5g and 11b were subjected to enzyme inhibition kinetics experiments,they were shown that the compound 5g and 11b were mixed inhibition type by plotting Lineweaver–Burk’s V^-1-[S]^-1 double reciprocal plot.Moreover,in order to better understand the mechanism of action about acetylcholinesterase inhibitory activity,the conformational analysis and molecular docking were carried out based on the principle of the four-point pharmacophore model necessary for acetylcholinesterase inhibition.In order to predict whether these compounds have the potential to become clinical drugs,and get insights into their pharmacokinetics profile,the compounds were subjected to in silico molecular property and ADMET（absorption,distribution,metabolism,excretion and toxicity）predictions using Molinspiration and PreADMET online servers,respectively.