期刊
MEDICINAL CHEMISTRY RESEARCH
卷 31, 期 5, 页码 705-719出版社
SPRINGER BIRKHAUSER
DOI: 10.1007/s00044-022-02869-z
关键词
Fluoroquinolone; Water-soluble; Antimicrobial activities; ADMET; Cytotoxicity
资金
- CAMS Innovation Fund for Medical Sciences [2019-I2M/-1-005/2021-I2M-1-052]
- Tianjin Key Technology RD Program [20YFZCSY00570]
- national Mega-project for Innovative Drugs [2019ZX09721001-006-001]
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.
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.
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