公开(公告)号：US20140088149A1

公开(公告)日：2014-03-27

申请号：US14088559

申请日：2013-11-25

申请人： Thioredoxin Systems AB

发明人： Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  Karuppasamy Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

IPC分类号： C07D421/04 ,  C07D293/12

CPC分类号： C07D421/04 ,  A61K31/381 ,  A61K31/41 ,  C07D293/12 ,  Y02A50/473

摘要： The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with Ki of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

摘要翻译： Ebselen的作用机制区分细菌和哺乳动物硫氧还蛋白还原酶（TrxR）。 它显示哺乳动物Trx的快速氧化，并且通过NADPH-TrxR催化依次硒硒酚与过氧化氢的周转，因此是哺乳动物抗氧化剂。 依布硒及其二硒化物是大肠杆菌TrxR的强竞争性抑制剂，Ki分别为0.14μM和0.46μM。 缺乏谷胱甘肽还原酶或谷胱甘肽的大肠杆菌突变体对依布硒林的抑制更敏感。 由于谷氧还蛋白或硫氧还蛋白系统是核糖核苷酸还原酶的电子供体，依普硒靶主要是谷胱甘肽和谷氧还蛋白阴性细菌，一类包括主要病原体。 因此，依布硒林和类似化合物可用作抗菌剂，即使对于多抗性菌株也是有用的。 以前不知道对ebselen，结核分枝杆菌（结核分枝杆菌）和幽门螺杆菌（胃溃疡和癌症）敏感的两种主要致病菌被证明是优异的靶标。 幽门螺杆菌对硫化硫也敏感。