Synthesis And Biological Activity Test Of 4-Arylthiazole-2-Amine Derivatives

Alzheimer's disease?Alzheimer's Disease, AD? is a degenerative disease of the nervous system. With the world's increasing aging population, the incidence of AD would be increased year by year. Currently, the most widely used treatment of AD drugs are acetylcholinesterase inhibitors?AChEI?. However, the current listed AChEI has such great toxic side effects that it's still unable to meet the clinical needs, so it's necessary to further develop new drugs.Under the direction of cholinergic hypothesis, N-?4-?4-methoxy-phenyl?thiazol-2-yl?-3-(pyrrolidin^-1-yl)propionamide which had a good inhibitory activity was used as a lead compound, 43 new 4-arylthiazole-2-amine derivatives were designed and synthesized, and their structure were confirmed by 1H NMR, MS and IR spectra. Their inhibiton activities to AChE in vitro were tested by Ellman spectrophotometry. The experiments results showed that most of the compounds had a certain AChE inhibition activity. And compounds 8b and 13 h had a better inhibition activity in vitro to AChE than other compounds. Their IC50 values are 8.73?mol·L^-1 and 0.15?mol·L^-1 separatively,which were superior to rivastigmine as the control drug. Especially the inhibition activity of compound 13 h to acetylcholinesterase was much higher than that of the lead compound, and the inhibiton activity to BuChE was little.In order to study the action mechanism of compound 13 h which held the best AChE inhibition activity,it's enzymatic kinetics experiments was tested. By plotting the V^-1-[S]^-1 double reciprocal curve of 13 h, it was found that the action mechanism of compound 13 h was a mixed type of competitive inhibition.