Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
J Med Chem. 2011 Jul 14;54(13):4600-10. doi: 10.1021/jm2002525. Epub 2011 Jun 3.
MurD ligase is one of the key enzymes participating in the intracellular steps of peptidoglycan biosynthesis and constitutes a viable target in the search for novel antibacterial drugs to combat bacterial drug-resistance. We have designed, synthesized, and evaluated a new series of D-glutamic acid-based Escherichia coli MurD inhibitors incorporating the 5-benzylidenethiazolidin-4-one scaffold. The crystal structure of 16 in the MurD active site has provided a good starting point for the design of structurally optimized inhibitors 73-75 endowed with improved MurD inhibitory potency (IC(50) between 3 and 7 μM). Inhibitors 74 and 75 showed weak activity against Gram-positive Staphylococcus aureus and Enterococcus faecalis. Compounds 73-75, with IC(50) values in the low micromolar range, represent the most potent D-Glu-based MurD inhibitors reported to date.
MurD 连接酶是参与肽聚糖生物合成细胞内步骤的关键酶之一,是寻找新型抗菌药物以对抗细菌耐药性的可行靶标。我们设计、合成并评价了一系列基于 D-谷氨酸的大肠杆菌 MurD 抑制剂,其中包含 5-亚苄基噻唑烷-4-酮骨架。16 在 MurD 活性部位的晶体结构为设计结构优化的抑制剂 73-75 提供了一个良好的起点,这些抑制剂具有改善的 MurD 抑制活性(IC50 在 3 到 7 μM 之间)。抑制剂 74 和 75 对革兰氏阳性金黄色葡萄球菌和粪肠球菌表现出较弱的活性。化合物 73-75 的 IC50 值在低微摩尔范围内,是迄今为止报道的最有效的基于 D-Glu 的 MurD 抑制剂。