Study On The Synthesis And Preliminary Activity Of Zidovudine Linked 1,2,3-triazole Derivatives

Hybrid antibacterial drugs become one of the most important methods for the development of antimicrobial drugs in recent years.Dihydrofolate reductase(DHFR)is an indispensable enzyme for bacteria,and it is regarded as an important drug target for antibacterial agents.In addition,pyrimidine derivatives have demonstrated good antibacterial properties,and the zidovudine structure contains a pyrimidine ring similar to Timethoprim(TMP).Pyrimidine and its derivatives are widely used in the synthesis of aromatic rings and heterocyclic compounds due to their extensive biological activity.Therefore,it is of great significance to study its synthesis and its application in the field of biomedicine.As an important N-heterocyclic block compound,1,2,3-triazole has been widely used in the fields of medicine,pesticide,materials and other fields.In order to search for new potential antibacterial compounds and based on our previous works,a series of novel 1,2,3-triazole derivatives that incorporate 3'-deoxythymidine were designed,synthesised and characterised.Furthermore,the antibacterial activity of the synthesised compounds against Escherichia coli and Staphylococcus aureus was evaluated,and preliminary structure–activity relationship studies are discussed.At the same time as conducting basic research,Mirabegron's process research was carried out during my degree studies.Mirabegron,is the first ?3-adrenergic receptor agonist discovered as a treatment for overactivity(OAB).The original process route requires high reaction conditions,complicated post-processing and high production costs,and is not suitable for industrial production.Thus,we reported a new,improved method to synthesize mirabegron.The research work of this thesis is divided into two parts:The first part: Zidovudine as the leader drug design,synthesis of 22 kinds of incorporation of 3'-deoxythymidine novel 1,2,3-triazole compounds.We optimized the reaction condition through the screening of the reaction solvent,the reaction temperature,catalyst and catalyst amount.The structures of the novel compounds were confirmed by 1H NMR,13 C NMR,and HRMS.The second part: The antibacterial activities of the 22 target compounds against Escherichia coli and Staphylococcus aureus were determined.The standard antibiotics streptomycin sulfate and doxycycline were used as controls.The results showed that some of the compounds showed good inhibitory effect on Escherichia coli.Among them,the target compounds 3e,3f,3h,3n,and 3o showed potential activity,and the MIC value was about 0.15 m M,which reached the same level as streptomycin sulfate.The structure-activity relationship of the target compounds was preliminary discussed and some of the compounds were molecularly docked.The appendix: With our new method,we used readily available starting material nitrophenylacetonitrile,(R)-1-phenyl-1,2-ethylene glycol,and ethyl 4-chloroacetoacetate and generated the title compound mirabegron with 99.6% purity and 61% overall yield.Our strategies are,first,to bypass the BH3-THF,DMI and intermediate product 5,hence reduce the formation of impurities in the catalytic nitro reduction steps;and second,to lower cost with the use of an inexpensive starting material This synthetic method has improved industrial feasibility with higher product purity,good yield,low cost,and easy operation.