Design,Synthesis And Of Anti-Herpes Simplex Virus Evaluation Of 3-Hydroxypyridones And Pyridine Hydroxamic Acids

Herpes simplex virus（HSV-1/2）belongs to the type A of human herpes virus（Human Herpes Virus,HHV）,that is,alpha-herpes virus.The treatment of HSV can only use drugs to intervene after the outbreak of the virus incubation period.The clinical first-line anti-HSV drugs are nucleoside analogs,such as acyclovir（ACV）,etc.However,clinical research finds that ACV has drug resistance problems.Therefore,the development of anti-HSV drugs based on new mechanisms has become the current research hotspot.In this thesis,a kind of hit compound Z-00 containing 3-hydroxypyridone structure skeleton was obtained through phenotypic screening,and the replication inhibition rate of HSV reached 73.86%at a concentration of 20μM.Based on this,we used the method of skeleton reuse to carry out diverse transformations with 3-hydroxypyridone as the skeleton to explore its structure-activity relationship,synthesized and transformed the first series of 19 compounds from Z-00 to Z-18,and carried out Structural characterization by HRMS,¹H-NMR and ¹³C-NMR.In the evaluation of the Vero cell model infected by HSV virus,we found that the virus inhibitory rate of the hit compound Z-16 reached 97.33%at 20μM,which was comparable to that of the positive compound ACV（98.05%at 20μM）.Therefore,the hit compound Z-16 was selected for the study of the antiviral dose-effect relationship(EC₅₀)and the evaluation of cytotoxicity.The results showed that the cytotoxicity of the hit compound Z-16 at a concentration of 20μM（cell survival rate 99%）was weaker than that of the positive compound ACV（cell survival rate 85%）.The EC₅₀ of the hit compound Z-16 was 5.667μM,and the EC₅₀ of the positive compound ACV was 0.086μM,showing certain anti-HSV activity.In this paper,the possible targets of the 3-hydroxypyridone series were further explored by molecular simulation docking.This type of structure contains a classic double-metal complex structure.In the life cycle of HSV virus,there are multiple kinds of two-metal ion-dependent proteases（Two-Metal Ion-Dependent enzymes,TMID）,which plays a key role in the process of DNA/RNA replication and transcription in the viral.Its key active site is mediated by two Mg²⁺or Mn²⁺.By complexing metal ions in the catalytic center,the purpose of inhibiting virus replication is achieved.Therefore,this work selects an important protein,DNA integrase,which plays a key role in the process of DNA replication,as the research target.The effect of 3-hydroxypyridone series on two metal ion-dependent enzymes was discovered through molecular simulation docking.It was found that this series of compounds can enter the protein pocket and complex the two Mg²⁺ions on the catalytic site,which will provide material basis for further research on the inhibition of TMID enzymes agents.In order to further explore the application of the double metal ion complex structure for anti-HSV,the third chapter of this paper uses 3-amino-2-pyridine hydroxamic acid as the core of the double metal coordination to design and synthesize the second series of H-01～H-09,consisting of a total of 9 compounds,using the method of skeleton reuse.All compounds were characterized by HRMS,¹H-NMR and¹³C-NMR,and screened for in vitro activity against HSV virus.In the evaluation of the Vero cell model infected by HSV virus,we found that the compound H-05 with the highest inhibitory rate in this series of compounds had only 38.73%inhibitory rate on the virus at 20μM,which was lower than that of 3-hydroxypyridone compounds.The results showed that the 3-hydroxypyridone backbone has potential anti-HSV activity.