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.
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The authors would like to kindly acknowledge the Ministry of Education and Science of the Russian Federation, government grant 20.9907.2017/VU (expert opinion, discussion, and paper preparation) and Russian Science Foundation No. 17-74-30012, IBG RAS Ufa (biological evaluation and compound selection).
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Ivanenkov, Y.A., Yamidanov, R.S., Osterman, I.A. et al. 2-Pyrazol-1-yl-thiazole derivatives as novel highly potent antibacterials. J Antibiot 72, 827–833 (2019). https://doi.org/10.1038/s41429-019-0211-y