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2-Pyrazol-1-yl-thiazole derivatives as novel highly potent antibacterials

The Journal of Antibiotics volume 72, pages 827–833 (2019)Cite this article

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Abstract

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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Acknowledgements

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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Authors and Affiliations

  1. Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Oktyabrya Prospekt 71, 450054, Ufa, Russia

    Yan A. Ivanenkov, Renat S. Yamidanov, Victor A. Terentiev, Mark S. Veselov, Andrey A. Ayginin, Sergey V. Sadovnikov, Rustam Matniyazov & Andrey Kh. Baymiev

  2. Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, 141700, Moscow, Russia

    Yan A. Ivanenkov, Vladimir A. Aladinskiy, Anastasia V. Aladinskaya, Victor A. Terentiev, Mark S. Veselov & Andrey A. Ayginin

  3. Lomonosov Moscow State University, Chemistry Department, Leninskie Gory, Building 1/3, GSP-1, 119991, Moscow, Russia

    Yan A. Ivanenkov, Ilya A. Osterman, Alexey E. Machulkin, Rostislav A. Petrov, Dmitry S. Bezrukov & Olga A. Dontsova

  4. ChemDiv, 6605 Nancy Ridge Drive, San Diego, CA, 92121, USA

    Yan A. Ivanenkov

  5. Skolkovo Institute of Science and Technology, Skolkovo, Russia

    Ilya A. Osterman, Petr V. Sergiev, Katerina S. Komarova, Dmitrii Lukianov, Svetlana Iarovenko, Dmitry S. Bezrukov & Olga A. Dontsova

  6. Lomonosov Moscow State University, Department of Chemistry, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow, Russia

    Petr V. Sergiev, Dmitry A. Skvortsov & Olga A. Dontsova

  7. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, Russia

    Katerina S. Komarova, Alina A. Sofronova & Svetlana Iarovenko

  8. Lomonosov Moscow State University, Faculty of Medicine, Moscow, Russia

    Alexander S. Malyshev

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Correspondence to Anastasia V. Aladinskaya.

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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

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  • DOI: https://doi.org/10.1038/s41429-019-0211-y

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