Design,Synthesis And In Vitro Activity Eva Luation Of 3-hydroxypyridinone Siderophor E-ciprofloxacin Conjugates And Construc Tion Of 2-Amino(Amine) Thiazoles Libraries

At present,the resistance of bacteria to antibiotics has become more serious in clinical practice,and there are fewer and fewer effective antibacterial agents to choose,and the time and money for developing new antibacterial agents are enormous.Siderophore—antibacterial agent conjugate is a potential strategy for solving bacterial drug resistance.It is the combination of siderophore and antibacterial agent through a linker to form a new molecule.This strategy cleverly uses bacterial siderophore-mediated iron uptake system.When the trivalent iron-siderophore complex is transported into the bacteria,the antibacterial agent is also transported into the bacteria to exert an antibacterial effect.This strategy is vividly called as "Trojan horse".In the first part,antibacterial agents and their drug resistance,siderophore-antibacterial agent conjugates and their mechanism of action have been reviewed.In the second part,we put forward the design idea of siderophore-antibacterial agent conjugates.On this basis,3-hydroxypyridinone was used as the siderophore,ciprofloxacin was used as the antibacterial agent,and three siderophore-antibacterial agent conjugates were synthesized by using a-amino acids with different chain length as the linker.Each compound was synthesized by five steps of linking protection group,substitution reaction,acid chloride reaction,condensation reaction and deprotection group.All of the synthesized target compounds were characterized by 1H NMR,13C NMR,HPLC-HRMS and melting point.In vitro activity evaluation,the designed compounds only had certain antibacterial activity against Klebsiella pneumoniae sensitive to ciprofloxacin,and ZY-2 and ZY-3 had lower activity than ZY-1.All three conjugates were not as good as the positive control of ciprofloxacin.Based on the result,it requires further compound design optimization and activity evaluation experiments.Construction compound libraries consisting of small molecule compounds is an important tool for the development of new drugs.2-amino(amine)thiazole structural unit has a wide range of biological activities and are present in many drugs.Therefore,the construction of a 2-amino(amine)thiazoles library is extremely important for the discovery of lead compounds.In the third part,we used synthon a-nitroepoxides with ammonium thiocyanate to develop one method for synthesising 2-aminothiazoles with advantages of available starting materials,mild reaction condition,simple operation and wide range of substrate adaptation.A total of 15 compounds were synthesized with a yield between 77 and 95%,and one of them is a new compound.Then we used synthon a-nitroepoxides with potassium thiocyanate and primary amine to develop one method for synthesising 2-aminethiazoles with advantages of "one-pot",mild reaction condition,simple operation and no additives required.A total of 12 compounds were synthesized with a yield between 65 and 90%,and nine of them are new compounds.We have proposed possible reaction mechanisms for the two new synthetic methods.The structure of all compounds was characterized by 1H NMR,13C NMR,HPLC-HRMS and melting point.