Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: Design, synthesis and evaluation as antibacterial agent
Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: Design, synthesis and evaluation as antibacterial agent
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新型3-芳基呋喃-2(5H)-单氟喹诺酮杂化物：抗菌剂的设计、合成和评价
DOI：
10.1016/j.bmc.2014.05.018
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发表时间：
2014-07-15
影响因子：
3.5
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
--
作者：
Wang, Xu-Dong;Wei, Wei;Zhu, Hai-Liang
3-芳基呋喃-2(5H)-one是一种靶向酪氨酰-tRNA合成酶(TyrRS)的新型抗菌药效团，与临床使用的氟喹诺酮类药物杂交，得到一系列新型多靶点抗菌药物。因此，合成了二十七个3-芳基呋喃-2(5H)-一-氟喹诺酮杂合体并评估了其抗菌活性。一些杂种表现出来自父母双方的优点，对包括革兰氏阴性和革兰氏阳性细菌在内的耐药菌株表现出广谱活性。抗菌测定中最有效的化合物 (11) 显示，对多重耐药大肠杆菌的 MIC50 为 0.11 μg/mL，比环丙沙星强约 51 倍。酶测定表明，11 是一种有效的多靶点抑制剂，针对 DNA 旋转酶的 IC50 为 1.15 +/- 0.07 muM，针对 TyrRS 的 IC50 为 0.12 +/- 0.04 muM。其对分离酶和完整细胞的优异抑制活性强烈表明 11 值得作为新型抗生素进行进一步研究。 (C) 2014 Elsevier Ltd. 保留所有权利。
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 0.11 mu g/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 +/- 0.07 mu M against DNA gyrase and 0.12 +/- 0.04 mu M 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. (C) 2014 Elsevier Ltd. All rights reserved.