Study On Design, Synthesis And Bioactivity Of 5h-thiazolo[3, 2-a]pyrimidine Derivatives

Alzheimer's Disease,discovered by Dr.Alois Alzheimer in1907,is described as a degenerative of the central nervous system(CNS).AD is a progressive disease,i.e.the onset of the disease may show mild symptoms,but these symptoms will sooner or later become more and more severe until the patient loses his or her capacity to handle normal daily activities.AD patients exhibit marked decline in cognitive ability and severe behavioral abnormalities such as irritability,anxiety, depression,disorientation and restlessness.Pathology study found that cholinergic system had a retrogression change in the brain of AD patients,and the AD patients' symptom could be improved when the concentration of ACh was increased.Acetylcholinesterase is an enzyme projecting into the synapse.It promotes the hydrolysis of the neurotransmitter acetylcholine at the cholinergic synapses with liberation of choline.Because of its central role in the neurotransmission system,the AChE has been attractive target for the rational design of mechanism-based inhibitors. According to the results of virtual screen,5H-thiazolo[3,2-a]pyrimidine derivatives were designed as acetylcholineterase inhibitor.23 target compounds were synthesized and characterized by ~1H-NMR,IR,GC-MS and LC-MS,among which 20 compounds were not yet reported in the literature.According to the Ellman experiments,in comparison to the neostigmine bromide,the inhibitory acetylcholineterase activitivies of the target compounds was tested.Some of the target compounds such as ethyl 3-(4-hydroxyphenyl)-7-methyl-5-propyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (CLM02),ethyl 3-(4-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM06),ethyl 3-(2-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 10),3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-ethanone(CLM15)showed potent inhibitory activitivies on acetylcholineterase;ethyl 3-(4-chlorophenyl)-7-methyl-5-propyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM03),ethyl 3,5-bis(4-methoxyphenyl)-7- methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate(CLM07),ethyl 3-(2-hydroxyphenyl)-5-phenyl-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 12),ethyl 3-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM22)showed inhibitory activity against acetylcholineterase.The structure and inhibitory activity relationship of target compounds were discussed.