In silico screening and synthesis of stable tilmicosin-hydrazone derivatives as potential DNA disruptors towards Staphylococcus aureus

Abstract

In this study, 30 tilmicosin-hydrazone derivatives were designed using MOE software. Six candidate molecules with strong binding affinity to DNA or DNA-Topo II complexes, as indicated by molecular docking results, were synthesized. These candidates were evaluated for their in vitro antibacterial activities against common Gram-positive and Gram-negative bacteria. Compounds Z-12 and Z-22 demonstrated superior inhibitory effects against most tested strains compared to reference drugs tilmicosin and erythromycin, with minimum inhibitory concentrations (MIC) of 1 μg/mL against S. aureus 25,923 and S. aureus 29,213. HPLC results indicated that Z-12 and Z-22 exhibited improved stability in acidic aqueous solutions compared to tilmicosin. UV–vis, fluorescence spectroscopy, and gel electrophoresis studies confirmed their intercalation into DNA base pairs via a static quenching mechanism. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) revealed irreversible oxidation processes on the glassy carbon electrode, providing insights into their potential metabolic pathways. Finally, a mouse wound infection model demonstrated that Z-12 and Z-22 exhibited good antibacterial efficacy, biocompatibility, and enhanced wound healing effects, surpassing those of tilmicosin. These findings, coupled with their prolonged metabolic half-life, highlight their potential as effective antibacterial agents.