Study On Design, Synthesis And Biological Activity Of Thiazolopyrimidine Derivatives

Alzheimer’s Disease（AD）,which is one type of senile dementia,can seriously injury the physical health of AD patients,with the aggravation of social ageing phenomena,AD gradually become a rigorous and complicated problem clinically and socially.Now it’s known that AD’s pathogen is very complicated and is relative to various factors,basically related to cellular senescence,neurotransmitter impairment and multiple genes deficient.Nowadays,there is still no complete recovery medicine for those AD patients,based on the current understanding of AD pathological mechanisms,a series of procedure has been generated to preventβ-amyloidprotein’s production,fabrication,deposition,and inflammatory reaction,which could cure or even prevent the AD.Acetylcholinesterase（AChE）inhibitors are one of the most promising therapies in treating and preventing AD,and are the most prescribed medicines clinically in use nowadays.But there are still many insufficiencies in today’s AChE inhibitors,such as pharmacodynamics, compliance and tolerance deficiency,consequently,the finding of new AChE inhibitors with improved efficacy and functional characteristics,has always been one of focuses in drug research and development recently.Based on the 3D structure of ACHE,with the analysis of receptor’s structure features and their interactive binding modes with reported ligands,according to the reported active ligands’ structures, using molecular docking strategy,the public internet compounds database（ZINC）and our private compounds database were virtually screened,a series of target compounds based on the virtual screen hits were designed and synthesized,and their respective AChE inhibitory activities in vitro were assayed.Firstly using a one pot Biginelli reaction to produce the 6-methyl-4-（4-hydroxyphenyl）-2-thia--1,2,3,4-tetrahydropyrimidine derivatives,then a Hantzsch-type condensation with substitutedα-phenacyl chlorides to form sixteen 5-（4-hydroxyphenyl）-5H-thiazolo[3,2-a]pyrimidine derivatives. These were later reacted to form fifty-five 5-（4-alkoxyphenyl）-5H-thiazolo[3,2-a]pyrimidine derivatives.The seventy-one target compounds structures were confirmed with MS,IR,¹H-NMR, ¹³C-NMR spectra.Therefore the optimal experimental parameters were determined:firstly the HCl-EtOH solution used in Biginelli and then the AcONa/AcOH buffer used in Hantzsch-type condensation.Searched in the SciFinder,all target compounds are unreported novel compounds. Adopted the Ellman method,in comparison to the neostigmine bromide,the assay of target compounds in the biological activity against freshly prepared human AChE in vitro were made,ten target compounds displayed considerable inhibitory effects with inhibition rates above 50%at 10μM,providing a starting point for development of novel drugs to treat Alzheimer’s disease.Based on the bioactivity results,a preliminary analysis and conclusion of their structure-activity relationship were summaried:（1）As to 5-（4-hydroxyphenyl）-5H-thiazolo[3,2-a] pyrimidines,the 5-（4-hydroxyphenyl）-6-acetyl-5H-thiazolo[3,2-a]pyrimidines are more potent than 5-（4-hydroxyphenyl）-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl esters.（2）As to 5-（4-alkoxyphenyl）-5H-thiazolo[3,2-a]pyrimidines,the substituted groups on C5 site dominate the structure-activity relationship,those hydrophobic and spatially large substituted groups show an enrichment effect.Searched in the SciFinder,the 5H-thiazolo[3,2-a]pyrimidines derivatives we designed are new type AChE inhibitors with brand-new scaffold features.