The present report describes our efforts to identify new structural classes of compounds having promising antibacterial activity using previously published double-reporter system pDualrep2. This semi-automated high-throughput screening (HTS) platform has been applied to perform a large-scale screen of a diverse small-molecule compound library. We have selected a set of more than 125,000 molecules and evaluated them for their antibacterial activity. On the basis of HTS results, eight compounds containing 2-pyrazol-1-yl-thiazole scaffold exhibited moderate-to-high activity against ΔTolC Escherichia coli. Minimum inhibitory concentration (MIC) values for these molecules were in the range of 0.037-8 μg ml-1. The most active compound 8 demonstrated high antibacterial potency (MIC = 0.037 μg ml-1), that significantly exceed that measured for erythromycin (MIC = 2.5 μg ml-1) and was comparable with the activity of levofloxacin (MIC = 0.016 μg ml-1). Unfortunately, this compound showed only moderate selectivity toward HEK293 eukaryotic cell line. On the contrary, compound 7 was less potent (MIC = 0.8 μg ml-1) but displayed only slight cytotoxicity. Thus, 2-pyrazol-1-yl-thiazoles can be considered as a valuable starting point for subsequent optimization and morphing.

中文翻译：

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2-吡唑-1-基噻唑衍生物是新型高效抗菌剂。

本报告介绍了我们使用先前发布的双报告系统pDualrep2来鉴定具有良好抗菌活性的化合物的新结构类别的努力。这种半自动化的高通量筛选（HTS）平台已应用于执行各种小分子化合物库的大规模筛选。我们已经选择了超过125,000个分子的集合，并对它们的抗菌活性进行了评估。根据HTS结果，包含2-pyrazol-1-yl-thiazole支架的8种化合物对ΔTolC大肠杆菌表现出中等到高的活性。这些分子的最小抑菌浓度（MIC）值在0.037-8μgml-1的范围内。活性最高的化合物8具有很高的抗菌效力（MIC = 0.037μgml-1），远远超过了红霉素的测定值（MIC = 2.5μgml-1），与左氧氟沙星的活性（MIC = 0.016μgml-1）相当。不幸的是，该化合物对HEK293真核细胞系仅表现出中等选择性。相反，化合物7的效力较低（MIC = 0.8μgml-1），但仅显示出轻微的细胞毒性。因此，2-吡唑-1-基噻唑可以被认为是后续优化和变形的有价值的起点。