First identification of isatin-β-thiosemicarbazones as novel inhibitors of New Delhi metallo-β-lactamase-1： Chemical synthesis, biological evaluation and molecular simulation  

作　　者：Guo-Qing Song Wei-Min Wang Zai-Shun Li Ying Wang Jian-Guo Wang 

机构地区：[1]State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, College of Chemistry, Nankai University, Tianjin 300071, China [2]Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China [3]Patent Examination Cooperation Jiangsu Center of the Patent Office, SIPO, Suzhou 215163, China

出　　处：《Chinese Chemical Letters》2018年第6期899-902,共4页中国化学快报（英文版）

基　　金：supported by the “111” Project of Ministry of Education of China (No. B06005);the National Natural Science Foundation of China (No. 21672114);the National Basic Research Program of China (No. 2013CB734004)

摘　　要：New Delhi metallo-b-lactmase-1（NDM-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC50 of 297.6 mmol/L. Based on this result, a series of isatin-β-thiosemicarbazones（IBTs）were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC50 values of 〈10 mmol/L, the best of which was 2.72 mmol/L. Comparative field analysis（Co MFA） contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors.New Delhi metallo-b-lactmase-1（NDM-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC50 of 297.6 mmol/L. Based on this result, a series of isatin-β-thiosemicarbazones（IBTs）were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC50 values of 〈10 mmol/L, the best of which was 2.72 mmol/L. Comparative field analysis（Co MFA） contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors.

关 键 词：New Delhi metallo-β-lactmase-1 Isatin-β-thiosemicarbazones In vitro enzyme inhibition Molecular docking 

分 类 号：TQ460.1[化学工程—制药化工]