Research On Design,synthesis And Activity Of Reversible Antiplatelet Aggregation Of Purine Nucleoside Derivatives

The serious impact of thrombotic diseases on human health has made antithrombotic drugs a current research focus.Purine nucleoside compounds based on the P2Y₁₂ receptor as a target not only have good antiplatelet aggregation activity,but also have the advantage of reversibility in the mechanism of interaction with organisms,which makes purine nucleoside drugs have good research prospects.This research paper has conducted a three-dimensional quantitative structure activity relationship（3D-QSAR）study on 51 purine nucleoside derivatives with antiplatelet aggregation activity.Three reliable computational models have been established using three research methods:Co MFA,Co MSIA,and SOMFA,and their prediction results have been verified.Based on the analysis of the obtained model,the following general rules of structure-activity relationships can be obtained:the compound site6 cannot be directly connected to a large volume of substituents.Instead,a linear transition structure should be connected at first,and then a large steric resistance substituent with a planar structure should be connected.Moreover,the high negative charge density in this region is conducive to activity;The position 2 is suitable for connecting medium volume substituents,and the high positive charge density of the long chain portion of the substituent is beneficial to activity;The hydroxyl group on the ribose ring is beneficial for activity because it can act as both a hydrogen bond acceptor and a hydrogen bond donor,and the introduction of a group with a high negative charge density and a large steric resistance at position 5’is beneficial for activity.The results provide an important basis for the molecular design of subsequent antiplatelet drugs.Based on the above rules,21 new compounds have been designed and reported.Using guanine nucleoside as raw material,two different synthesis routes have been successfully explored,and some reactions have been refined and optimized to avoid the formation of by-products and improve the synthesis efficiency.Purine nucleoside derivatives with benzene and ethylamine long chain structures at purine ring position 6 and Schiff base purine nucleoside derivatives with benzene and C=N conjugated double bond structures at puring ring position 6 were synthesized through the protection of ribose acetylation,chlorination of purine ring position 6,alkylation of purine ring position 2,and two different processing modifications of purine ring position 6.The 21 compounds were characterized by ¹H NMR,¹³C NMR,IR,and HRMS.In the future,this article will test the anti platelet aggregation activity of the synthesized new compounds.