Synthesis and Biological Evaluation of Diphenyl Ether-Linked Quinolone Derivatives as Antibacterial Agents

The increase in the prevalence of multi-drug-resistant bacteria poses a significant healthcare challenge. The urgent need to combat the resistant microbes necessitates discovering new antibacterial agents capable of circumventing the existing resistance mechanisms. Targeting DNA gyrase by suitably modifying the fluoroquinolones can lead to antibiotics with better activity and lower incidence of resistance. The substituted diphenyl ethers like triclosan are known to have potent antibacterial activity. In the current study, the hybridisation of diphenyl ether moiety with fluoroquinolones led to the design and synthesis of new compounds with potent inhibitory activity against staphylococcus aureus with MIC 0.5-64 mu g/mL and moderately active against mycobacteria with MIC 2-64 mu g/mL. The compounds are non-toxic to Vero cells with a selectivity index >10 to 200. The compounds also inhibited the resistant strains of S. aureus with a MIC ranging from 0.5-64 mu g/mL. The synthesised compounds also exhibited potent anti-biofilm activity against S. aureus. Furthermore, the DNA supercoiling assay revealed the compounds 7 i, 7 o, 7 p and 7 q showed concentration-dependant DNA-Gyrase inhibition at 1 mu g/mL.