Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Arch Pharm (Weinheim). 2018 Jan;351(1). doi: 10.1002/ardp.201700333. Epub 2017 Dec 14.
Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2,6-diamine, 2-(2-aminothiazol-4-yl)acetic acid, and benzo[1,2-d]thiazole-2,6-diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo[1,2-d]thiazoles 32-34, 36, and 37 with IC values in the low micromolar range. The most promising inhibitors identified were evaluated against selected Gram-positive and Gram-negative bacterial strains. Compound 33 showed a MIC of 50 μM against an E. coli efflux pump-defective strain, which suggests that efflux decreases the on-target concentrations of these compounds.
发现新型 DNA 拓扑异构酶 B 抑制剂仍然是寻找新的抗菌药物以克服已知细菌耐药机制的一个有吸引力的领域。在本研究中，我们设计并合成了新型 4,5,6,7-四氢苯并[1,2-d]噻唑-2,6-二胺、2-(2-氨基噻唑-4-基)乙酸和苯并[1,2-d]噻唑-2,6-二胺的乙基脲衍生物，并评估了它们对大肠杆菌 DNA 拓扑异构酶的抑制作用。在所制备的化合物库中，最有效的 DNA 拓扑异构酶抑制剂是苯并[1,2-d]噻唑 32-34、36 和 37，其 IC 值在低微摩尔范围内。所鉴定的最有前途的抑制剂针对选定的革兰氏阳性和革兰氏阴性细菌菌株进行了评估。化合物 33 对大肠杆菌外排泵缺陷株的 MIC 为 50 μM，这表明外排降低了这些化合物的靶浓度。
