Study On Synthesis And Biological Activity Of Thiazolopyrimidine Derivatives And Analogues

Alzheimer’s Disease(AD),is a disease of the central nervous system,a degenerative disease, with the progressing cognitive disorder and the decrescence of memory.The most obvious manifestation is dementia.The main pathophenomenon is cerebral atrophy,β-amyloid and neurofibrillary tangles of the brain tissue.Acetylcholinesterase is the most critical enzyme during the nerve conduction of the organism. It is found between the cholinergic synapse,and its function is to make degradation of the acetylcholine.Cerebral atrophy,β-amyloid and neurofibrillary tangles of the brain tissue induce the lack of acetylcholine.Inhibiting the activity of the AD patients’ acetylcholine,it will prolong the exist time of the acetylcholine.Then,the content of the acetylcholine in the brain will be increased. So,acetylcholine has already been the target enzyme,which is relevant with the acetylcholine inhibitor designed widespreadly.We have studied the 3-dimensional structure and function of acetylcholine,and use the methode of Computer Aided Drug Design.The feature of the receptor is analysised and the relationship between receptor and ligand is studied,too.In accordance with the structure of existent active ligands,we dock the dummy compound library and make dummy selections.A series of thiazolo[3,2-a]pyrimidine derivatives and their analogs are been designed.They have never been reported as the acetylcholinesterase inhibitor.We have synthesized 18 compounds.They are 9 compoundes of 3-oxo-2,3-dihydro-5H-thiazol o[3,2-a]pyrimidine derivatives,5 compoundes of 4-oxo-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3] thiazine derivatives and4compoundes of 4-oxo-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine derivatives.All compounds we synthesized have been determined by NMR,MS and IR.Among these compounds.After retrieveing SciFinder,we find that there are 12 compounds which have not been reported.Some of the target compounds are screened as the acetylcholinesterase inhibitor by Ellman method in vitro.The results indicate that the compounds we designed all have the activities during inhibiting acetylcholine,as the same as the presumption.The mean inhibitions of 6-acetyl-5-(4-me thoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-3-one,5-phenyl-7-methyl-3-oxo-2,3-dihydro -5H-thiazolo[3,2-a]pyrimidin-6-carboxylicacid ethyl ester,6-(4-methoxyphenyl)-8-methyl-4-oxo -3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxylicacid ethyl ester,7-acetyl-6-(4-methoxyphenyl)-8-methyl-2,3-dihydro-6H-pyrimido[2,1-b][1,3]thiazin-4-one,8-methyl-6-phenyl-3, 4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxylicacid ethyl ester and 8-methyl-6-phenyl-3, 4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxylicacid ethyl ester have been above 50%.