Synthesis, antibacterial evaluation and in silico study of DOTA-fluoroquinolone derivatives

A series of water-soluble fluoroquinolones based upon DOTA (1,4,7,10-tetraazacyclododecane -1,4,7,10-tetraacetic acid) modification were synthesized and characterized by NMR and HRMS spectra. All the newly prepared quinolones compounds exhibited potent antimicrobial activities against MRSA (methicillin-resistant Staphylococcus aureus), P. aeruginosa and E. coli. Molecular docking study indicated they could form stable complex with DNA gyrase and topoisomerase IV-DNA respectively, ADMET prediction showed they were low toxicity to the mice as whole. Among them, water-soluble quinolone 4c exhibited promising antibacterial potency, its MIC, MBC value for MRSA and P. aeruginosa was (1.56, 6.25) mu g/mL, (3.1, 12.5) mu g/mL respectively. Atomic Force Microscope (AFM) imaging revealed 4c could effectively destroy MRSA bacterial membrane and wall, causing its contents to leak out. Cytotoxicity assay showed 4c had low toxicity to L-02, A549 and MCF-7, over 80% cell viability even at 100 mu mol/L. These results showed that water-soluble compound 4c was a promising antibacterial candidate.

Automated summary

A series of water-soluble fluoroquinolones based on DOTA modification were synthesized and characterized. These compounds exhibited potent antimicrobial activities against MRSA, P. aeruginosa, and E. coli. Among them, water-soluble quinolone 4c showed promising antibacterial potency with low cytotoxicity.