Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure-activity relationships of ureido-heterocyclic-carboxylic acids
Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure-activity relationships of ureido-heterocyclic-carboxylic acids
复制标题
DOI：
10.1039/c3ra45820b
复制
发表时间：
2014-01-01
期刊：
影响因子：
3.9
通讯作者：
Hartmann, Rolf W.
中科院分区：
文献类型：
--
作者：
Elgaher, Walid A. M.;Fruth, Martina;Hartmann, Rolf W.
细菌耐药性的出现需要开发具有替代作用模式的新抗生素。在我们前期研究开发的第一类RNA聚合酶抑制剂的基础上，设计了一系列靶向于开关区的RNA聚合酶抑制剂。开发了芳基脲基杂环羧酸的可行合成方法，包括三种区域异构的噻吩类（II-IV），以及三种电子等排的呋喃（V，VI）和噻唑（VII）类。使用RNAP转录抑制测定的生物学评价显示，II类化合物具有与母体I类相同的活性，而III类、V-VII类化合物具有活性，但效力较低。分子建模支持的构效关系（SAR）研究阐明了与结合位点相互作用所需的结构要求。除RNAP抑制作用外，新化合物对革兰氏阳性菌和革兰氏阴性E. coliTolC菌株。此外，它们与临床使用的RNAP抑制剂利福平（Rif）没有交叉耐药性，并且与Rif相比耐药率较低。
The emergence of bacterial resistance requires the development of new antibiotics with an alternative mode of action. Based on class I, developed in our previous study, a new series of RNA polymerase (RNAP) inhibitors targeting the switch region was designed. Feasible synthetic procedures for the aryl-ureido-heterocyclic-carboxylic acids were developed including three regioisomeric thiophene classes (II-IV), as well as three isosteric furan (V, VI) and thiazole (VII) classes. Biological evaluation using a RNAP transcription inhibition assay revealed that class II compounds possess the same activity as the parent class I, whereas classes III, V-VII were active, however with lower potency. Structure-activity relationship (SAR) studies, supported by molecular modeling, elucidated the structural requirements necessary for interaction with the binding site. Beside the RNAP inhibitory effects, the new compounds displayed good antibacterial activities against Gram positive bacteria and the Gram negative E. coli TolC strain. Moreover, they showed no cross resistance with the clinically used RNAP inhibitor rifampicin (Rif) and a lower rate of resistance compared to Rif.