Synthesis And Biological Activity Of Uracil And Oxadiazole Derivatives

This thesis mainly research work for the following two aspects:Chapter Ⅰ:With uracil oxime compounds and adjacent chlorobenzene formaldehyde as raw material,reaction with sodium hydroxide base,Na OH do with（Me OH:DMF=5 to 1）mixed solvent as reaction solvent,and the reaction at room temperature,the synthesis of a series of 1-（aryl aldehyde oxime）uracil derivatives were a total of 32 compounds were synthesized by this method.All of the 32 compounds were characterized by ¹H NMR,¹³C NMR,IR and HRMS.To further verify the conformation of the compound,we chose one of the compounds for single crystal culture and determined the structure of the compound.Some of our uracil compounds were tested for thymidine phosphorylase（TP）inhibitory activity.Among them,compounds I-f4,I-f5,I-f6,I-f7 and I-f12 showed very good thymidine phosphorylase inhibitory activity with IC₅₀values between 0.12±0.05and 7.2±1.4μM.In addition,the compounds I-f1,I-f8,I-f9,I-f10,I-f13,I-f14,I-f15,I-f17,I-f19,I-f20,and I-f21 behave.A superior inhibitory activity（IC50 from 10.7 to39.9μM）was demonstrated.The kinetic experiment was performed using the best active compound I-f12 in this series.The results showed that the compound exhibited competitive inhibition kinetics.Molecular docking experiments showed that the interaction of these newly synthesized compounds with the active site of thymidine phosphorylase was consistent with the activity test results.In general,experiments have shown that these compounds are promising thymidine phosphorylase（TP）inhibitors.Chapter Ⅱ:In the previous work of our research group,we found a group of heterocyclic compounds containing 1,2,4 oxadiazole ring structure,and had a very good cancer cell inhibitory activity,but we found this reaction during the experiment.The yield is low and it is not easy to separate.In order to solve these problems,we further optimized the reaction conditions and found that when the copper ion promoter was added and the reaction temperature was increased,the yield of the reaction was significantly improved.We usedα-chlorobenzaldehyde oxime and quinazolinedione as reaction materials,mixed solvent（DMSO:Me OH=2:1）as the reaction solvent,Cs₂CO₃ as base,and Cu SO₄ as the accelerant of the reaction at 68°C.We used this method to synthesize a total of 15 compounds.