Zhang Yi-Lin, Yan Yong, Wang Xue-Jun, Yang Ke-Wu
College of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, China.
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, China.
Antibiotics (Basel). 2020 Feb 26;9(3):99. doi: 10.3390/antibiotics9030099.
Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent. Biological activity assays identify the thiazolethioacetamides can inhibit ImiS with IC values of 0.17 to 0.70 μM. For two of them, the IC values against VIM-2 were 2.2 and 19.2 μM, which is lower than in our previous report. Eight of the thiazolethioacetamides are able to restore antibacterial activity of cefazolin against -ImiS by 2-4 fold. An analysis of the structure-activity relation and molecule docking show that the style and position of electron withdrawing groups in aromatic substituents play a crucial role in the inhibitory activity of thiazolethioacetamides. These results indicate that thiazolethioacetamides can serve as a potential skeleton of MβL inhibitors.
金属β-内酰胺酶（MβLs）介导的抗生素耐药性严重威胁着细菌性疾病的治疗。最近，我们发现硫代乙酰胺类化合物可能是一种潜在的MβL抑制剂骨架。为了完善该骨架的信息，通过修饰芳香取代基设计了12种新型噻唑硫代乙酰胺类化合物。生物活性测定表明，噻唑硫代乙酰胺类化合物能够抑制ImiS，其IC值为0.17至0.70μM。其中两种化合物对VIM-2的IC值分别为2.2和19.2μM，低于我们之前的报告。八种噻唑硫代乙酰胺类化合物能够使头孢唑林对-ImiS的抗菌活性恢复2至4倍。结构-活性关系分析和分子对接表明，芳香取代基中吸电子基团的类型和位置对噻唑硫代乙酰胺类化合物的抑制活性起着关键作用。这些结果表明，噻唑硫代乙酰胺类化合物可作为MβL抑制剂的潜在骨架。
