Synthesis and biological evaluation of ruthenium polypyridine complexes with 18β-glycyrrhetinic acid as antibacterial agents against Staphylococcus aureus

Abstract

Four new ruthenium(II) polypyridine complexes bearing 18β-glycyrrhetinic acid derivatives, [Ru(bpy)₂L](PF₆)₂ (Ru1), [Ru(dmb)₂L](PF₆)₂ (Ru2), [Ru(dtb)₂L](PF₆)₂ (Ru3) and [Ru(phen)₂L](PF₆)₂ (Ru4) (bpy = 2,2-bipyridine, dmb = 4,4′-dimethyl-2,2′-bipyridine, dtb = 4,4′-di-tert-butyl-2,2′-bipyridine, phen = 1,10-phenanthroline and L is the GA modified new ligand) were designed and synthesized. Their antimicrobial activities against Staphylococcus aureus (S. aureus) were evaluated and all complexes showed an obvious inhibitory effect, especially, the minimum inhibitory concentration (MIC) value of Ru2 was 3.9 μg mL⁻¹. Moreover, Ru2 was found to significantly inhibit the formation of biofilms. The membrane-compromising action mode was suggested to be their potential antibactericidal mechanism. In hemolysis experiments, Ru2 hardly showed cytotoxicity to mammalian erythrocytes. Furthermore, the synergism between Ru2 and common antibiotics, such as ampicillin, chloramphenicol, tetracyclines and ofloxacin, against S. aureus was also detected using the checkerboard method. Finally, a mouse skin infection model was established to evaluate the antibacterial activity of Ru2in vivo, and the results showed that Ru2 could effectively promote wound healing in mice infected with S. aureus. Moreover, the results of histopathological research were consistent with the results of the hemolysis test, indicating that the Ru2 complex was almost non-toxic. Thus, it was demonstrated that the polypyridine ruthenium complexes modified with glycyrrhetinic acid (GA) are a promising strategy for developing interesting antibacterial agents.