Rhodanine as a Potent Scaffold for the Development of Broad Spectrum Metallo-beta-lactamase inhibitors
Rhodanine as a Potent Scaffold for the Development of Broad Spectrum Metallo-beta-lactamase inhibitors
复制标题
绕丹宁作为开发广谱金属-β-内酰胺酶抑制剂的有效支架
DOI：
10.1021/acsmedchemlett.7b00548
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发表时间：
2018
影响因子：
4.2
通讯作者：
He Yuan
中科院分区：
文献类型：
--
作者：
Xiang Yang;Chen Cheng;Wang Wen Ming;Xu Li Wei;Yang Ke Wu;Oelschlaeger Peter;He Yuan
合成了一系列绕丹宁，通过小分子X-射线衍射确定了它们的Z-构型，并测定了它们对金属β-内酰胺酶（MβLs）的活性。26个化合物和1个硫代烯醇化物对MβL L1有特异性抑制作用，IC_（50）为0.02-1.7 μM; 2 h ~ m对Mβ L NDM-1、Vim-2、ImiS和L1有广谱抑制作用，IC_（50）<16 μM。所有抑制剂均能增强头孢唑啉对E的抗菌作用。表达L1的大肠杆菌，导致MIC降低2-8倍。对接研究表明，2l的硝基（NDM-1，CphA和L1）或羧基（Vim-2）与一个或两个Zn（II）离子配位，而抑制剂的N-苯基增强了其与MβLs的疏水作用。这些研究表明，二芳基取代的绕丹宁类化合物是一种很好的骨架化合物，可用于设计MβLs的广谱抑制剂。
A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the MβL L1 with an IC50range of 0.02–1.7 μM, and compounds2h–mexhibited broad-spectrum inhibition of the MβLs NDM-1, VIM-2, ImiS, and L1 with IC50values <16 μM. All inhibitors increased the antimicrobial effect of cefazolin againstE. colicells expressing L1, resulting in a 2–8-fold reduction in MIC. Docking studies suggested that the nitro (NDM-1, CphA, and L1) or carboxyl group (VIM-2) of2lcoordinates one or two Zn(II) ions, while theN-phenyl group of the inhibitor enhances its hydrophobic interaction with MβLs. These studies demonstrate that the diaryl-substituted rhodanines are good scaffolds for the design of future broad-spectrum inhibitors of MβLs.