Design, synthesis, and evaluation of novel fluoroquinolone-flavonoid hybrids as potent antibiotics against drug-resistant microorganisms.
Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position.
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: xiaozhuping2005@163.com.
Zhu-Ping
ZP
Xiao
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Xu-Dong
XD
Wang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Peng-Fei
PF
Wang
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Yin
Y
Zhou
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Jing-Wen
JW
Zhang
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Lei
L
Zhang
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Jiao
J
Zhou
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Sha-Sha
SS
Zhou
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Hui
H
Ouyang
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Xiao-Yi
XY
Lin
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Manzira
M
Mustapa
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
Asaimuguli
A
Reyinbaike
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China. Electronic address: zhuhl@nju.edu.cn.
Hai-Liang
HL
Zhu
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002176:Candida albicans / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005419:Flavonoids / Q000737:chemistry*; D024841:Fluoroquinolones / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D004278:DNA, Superhelical; D005419:Flavonoids; D024841:Fluoroquinolones; D027081:DNA Gyrase
DNA gyrase; Efflux pump; Flavonoid; Fluoroquinolone; Hybrid; Inhibitor