De Novo Molecular Design Of Purine Derivatives And Synthesis Of New 8-azapurine Derivatives

Purine pharmacophores have been found in antiviral,antitumor,antiplatelet aggregation,and other drug molecules.Purine is the basic skeleton of important derivatives in medicine and has been extensively studied in pharmaceutical chemistry.In this paper,a series of molecular design and synthesis studies were carried out around the purine,which provided a research basis for the molecular design of the anticoagulant drug purine derivatives and the synthesis of 8-azapurine derivativesFirst,the structure-activity relationship(SAR)between the structures of 68 purine derivatives and their anti-platelet aggregation activities was analyzed.The SAR result indicated that these purines which were substituted by sulfur hydrocarbon at 2-position,slender groups such as phenethylamine group at 6-position,hydrophilic groups such as hydroxyl at 9-position,had higher anticoagulant activity.Then,the 39 purine derivatives were subjected to SOMFA study which indicated that these purines which retain 3 carbon atoms in length at 2-position,connecting a medium-length group at 6-position,introducing longer chain into 9-position were conducive to the improvement of the activity.Besides,base on literatures,the molecular structures databases of purine derivatives were established homologously and performed de novo molecular design research.The result indicated that these purines which were substituted by a chlorine atom,a methylthio group or benzene ring long-chain of hydrophilic groups such as amino group,carboxyl group at 2-position,introducing a monosubstituted amine at the 6-position,and not directly connected to the benzene ring or amide,introducing hydrophilic groups such as hydroxyl group,carboxyl group,phosphoric group,amide at the 9-position or introducing sugar ring structure whose 5’ position was connected with hydrophilic groups such as phosphate group,carboxylic acid group,sulfonamide group,was conducive to the improvement of the activity.Finally,combined with theoretical analysis,32 unreported modified 8-azapurine derivatives at positions 6,9 were designed and synthesized and characterized by 1H NMR,13C NMR,and IR.