Synthesis And Antibacterial Activity Of Metal Complexes Derived From Sulfadiazine

The discovery and invention of antimicrobial drugs are one of the greatest milestones in the field of modern medicine and pharmacology,and humans have used antimicrobial drugs to treat a range of diseases caused by bacterial infections.Sulfonamides are a representative class of chemically synthesized antimicrobial drugs that have been used in clinical for more than 80 years,and its mechanism of action is the inhibition of bacterial folate metabolism,thereby affecting the growth and reproduction of bacteria.Sulfonamides are used in veterinary clinics because of their broad antibacterial spectrum,simple use,stable nature,wide distribution in vivo and other advantages.However,sulfonamides have weak antibacterial activity,no bactericidal effect,more side effects,and easily lead to resistance of S.aureus and E.coli,which makes the use of sulfonamides in clinical practice gradually reduced.In recent years,many scholars have made structural modifications of sulfonamides in order to find high antibacterial activity and low side effects of sulfonamide drugs at home and abroad.Metal complexes derived from sulfonamides can improve the antibacterial activity due to increasing the lipid solubility of sulfonamides which is conducive to penetrating the cell membrane and entering into the cell.So research content of this paper mainly includes the following aspects:1.Schiff base ligand L₁ derived from pyridine-2-carbaldehyde and sulfadiazine,and L₂ derived from salicylaldehyde and sulfadiazine were synthesized and characterized by UV,IR,¹H NMR and HRMS.Six metal complexes of Zn L₁,Cu L₁,Co L₁,Zn L₂,Cu L₂,Co L₂ with Schiff base ligand L₁ and L₂ were synthesized and characterized by UV,IR,elemental analysis and thermogravimetry.The diameter of the inhibition circle,minimum inhibitory concentration（MIC）and minimum bactericidal concentration（MBC）of Schiff base ligands and metal complexes were measured by Oxford cup method,twofold dilution method and plate counting method.The results showed that the inhibitory activity of the ligands and complexes against E.coli and S.aureus was better than that of sulfadiazine（SD）.Moreover,Zn L₁ complex had not only better antibacterial activity but also bactericidal activity,and MIC was 0.5 mg/m L（4 times higher than that of SD）for both E.coli and S.aureus,and MBC was 1mg/m L.The effects of Zn L₁ on the bacterial growth curves of E.coli and S.aureus were measured by photoelectron turbidimetry.The experimental results showed that Zn L₁ could delay the arrival of bacterial logarithmic phase at low concentrations effectively and inhibit the growth of bacteria at high concentrations completely.2.Three ternary metal complexes of Zn[（Kae）（SD）],Cu[（Kae）（SD）] and Co[（Kae）（SD）])with ligands SD and Kae were synthesized and characterized by UV,IR,elemental analysis and thermogravimetry.The diameter of the inhibition circle,minimum inhibitory concentration（MIC）and minimum bactericidal concentration（MBC）of three ternary metal complexes were measured by Oxford cup method,twofold dilution method and plate counting method.The results showed that the ternary metal complexes had better bactericidal activity against both E.coli and S.aureus than SD and Kae.Moreover Zn[（Kae）（SD）] complex had the best antibacterial activity and bactericidal activity,and MIC was 0.125 mg/m L for both E.coli and S.aureus（16 times higher bactericidal activity compared to SD）and MBC was 0.125mg/m L for E.coli and S.aureus.The MBC was 0.25 mg/m L for E.coli and 0.5 mg/m L for S.aureus.The effects of Zn[（Kae）（SD）] on the bacterial growth curves of E.coli and S.aureus was measured by photoelectron turbidimetry.The experimental results showed that the complexes could delay the arrival of bacterial logarithmic phase at low concentrations effectively and inhibit the growth of bacteria at high concentrations completely.On this basis,the effects of Zn[（Kae）（SD）] on the cell walls and cell membranes of E.coli and S.aureus bacteria were measured by AKP viability assay,Coomassie Brilliant Blue G-250 method,and ONPG colorimetric method.The experimental results showed that Zn[（Kae）（SD）] can increased the AKP content,protein content,and β-galactosidase content in E.coli and S.aureus bacterial suspensions relative to the blank and SD groups significantly,it can show that after the compound interacts with bacteria,it may demage the integrity of the bacterial cell wall and cell membrane structure,increased the permeability of cell membrane,made intracellular substances flowed out,and finally lead to the death of bacteria.In summary,a series of sulfadiazine-derived Schiff base metal complexes and ternary metal complexes were synthesized,and Zn[（Kae）（SD）] was screened to have the strongest antibacterial activity and bactericidal activity.The mechanism of Zn[（Kae）（SD）] inhibition was initially investigated,and the metal complexes were found to have significant effects on the integrity of both cell wall and cell membrane structures.The research in the paper lays the pharmacological foundation for improving the clinical application of sulfadiazine-derived metal complexes and also provides new ideas for the modification of other sulfonamides.