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Bioorg Med Chem. 2014 Jul 15;22(14):3620-8. doi: 10.1016/j.bmc.2014.05.018. Epub 2014 May 20.

Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: design, synthesis and evaluation as antibacterial agent.

Author information

1
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China.
2
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
3
College of Biology and Environmental Science, Jishou University, Jishou 416000, PR China.
4
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China. Electronic address: xiaozhuping2005@163.com.
5
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, PR China. Electronic address: oyhmail@163.com.
6
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.

Abstract

3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11μg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07μM against DNA gyrase and 0.12±0.04μM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.

KEYWORDS:

3-Arylfuran-2(5H)-one; DNA gyrase; Fluoroquinolone; Hybrid; Multi-target; TyrRS

PMID:
24882676
DOI:
10.1016/j.bmc.2014.05.018
[Indexed for MEDLINE]

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