Design And Synthesis Of Biphenyl Group Modified Antibacterial Ruthenium/Iridium Complexes And Anti-infective Activity Study

Pathogenic bacteria pose a huge threat to human health.According to the prediction of the WHO,if the development of drug-resistant bacteria is not curbed,10million people will die from bacterial infections worldwide by 2050.Therefore,new strategies are urgently needed to deal with antibiotics resistance.Metals have long been applied in the history of human antibacterial.Thousands of years ago,ancient people used metal silver vessels to preserve food and silver needles for acupuncture to avoid bacterial infections.Recently.metal ruthenium and iridium complexes have attracted extensive attention due to their significantly antibacterial activities.In our study,ruthenium and iridium were taken as the core,introducing some key active function groups to modify it,new compounds with significant antibacterial advantages are screened,and the antibacterial mechanism of compounds is deeply studied.The main research content includes the following points:1.Synthetic four ligands（L1,L2,L3 and L4）and cis-Ru（bpy）₂Cl₂,cis-Ru（phen）₂Cl₂,cis-Ru（dmp）₂Cl₂,cis-Ru（dmb）₂Cl₂,cis-Ru（dtb）₂Cl₂,cis-Ru（btp）₂Cl₂,cis-Ru（ncp）₂Cl₂,cis-Ru（tmp）₂Cl₂ reaction obtained 14 metal ruthenium complexs.Ru1:[Ru（bpy）₂L3]（PF₆）₂,Ru2:[Ru（phen）₂L3]（PF₆）₂,Ru3:[Ru（dmp）₂L3]（PF₆）₂,Ru4:[Ru（phen）₂L1]（PF₆）₂,Ru5:[Ru（phen）₂L2]（PF₆）₂,Ru6:[Ru（phen）₂L4]（PF₆）₂,Ru7:[Ru（dmb）₂L3]（PF₆）₂,Ru8:[Ru（dtb）₂L3]（PF₆）₂,Ru9:[Ru（dtp）₂L3]（PF₆）₂,Ru10:[Ru（dmb）₂L1]（PF₆）₂、Ru11:[Ru（dmb）₂L2]（PF₆）₂,Ru12:[Ru（dmb）₂L4]（PF₆）₂,Ru13:[Ru（phen）₂L3]（PF₆）₂,Ru14:[Ru（phen）₂L3]（PF₆）₂.The structure of complexes Ru1-Ru14 was characterized.The inhibition of S.aureus activity was tested,and it was found that Ru2 antibacterial activity was the best（MIC of 2μg/m L,MBC of 4μg/m L）.In the time-killing kinetics data shows,Ru2 could rapidly kill S.aureus.In addition,Ru2 can effectively inhibit the formation of bacterial biofilms and the secretion of hemolytic toxins.We have proved the antibacterial mechanism of Ru2 through the experiments such as fluorescent staining,scanning microscopy,DNA leakage that Ru2targets the bacterial cell membrane to destroy bacterial cell membrane integrity and kill bacteria.It is found that it is difficult to produce drug resistance to Ru2 through a drug-resistant induction experiment.In the animal infection model,Ru2 has significant antibacterial activity in vivo.In the end,the security assessment of Ru2 shows that Ru2has low toxicity under the dosage.2.[Ir（ppy）₂Cl]₂ containing iridium was synthesized.[Ir（ppy）₂Cl]₂ and L1,L2,L3,L5 reaction obtained Ir1:[Ir（ppy）₂L1]PF₆,Ir2:[Ir（ppy）₂L2]PF₆,Ir3:[Ir（ppy）₂L5]PF₆,Ir4:[Ir（ppy）₂L3]PF₆ four iridium complexes,of which ppy is 2-phenylpyridine and[Ir（ppy）2Cl]2 is regarded as Ir.The structure of complexes Ir1-Ir4 were characterized by HRMS spectrometry,and ¹H-NMR and ¹³C-NMR spectra and HRMS spectra.Then,its antibacterial ability for S.aureus was measured,Ir3 was the best the antibacterial ability,MIC is 2μg/m L.In addition,Ir3 has good stability in blood,serum,plasma.Rabbit red blood cell hemolysis test data shows that Ir3 can inhibit the production of bacterial hemolytic toxin.By inhibiting the biofilm activity test,Ir3 can inhibit the formation of bacterial biofilms and eradicate the formed biofilm.In chessboard experiments showed,Ir3 could enhanced antibacterial activity of gentamicin（FICI=0.3125）,colistin B（FICI=0.3125）,and tetracycline（FICI=0.5）.In the animal skin infection model,Ir3 is found to kill bacteria and promote the healing of mouse epidermal trauma.