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

Ivanenkov, Y.A.; Yamidanov, R.S.; Osterman, I.A.; Sergiev, P.V.; Aladinskiy, V.A.; Aladinskaya, A.V.; Terentiev, V.A.; Veselov, M.S.; Ayginin, A.A.; Skvortsov, D.A.; Komarova, K.S.; Sadovnikov, S.V.; Rustam, M.; Sofronova, A.A.; Malyshev, A.S.; Machulkin, A.E.; Petrov, R.A.; Dmitrii, L.; Svetlana, I.; Bezrukov, D.S.; Baymiev, A.K.; Dontsova, O.A.

Авторы: Ivanenkov Yan A., Yamidanov Renat S., Osterman Ilya A., Sergiev Petr V., Aladinskiy Vladimir A., Aladinskaya Anastasia V., Terentiev Victor A., Veselov Mark S., Ayginin Andrey A., Skvortsov Dmitry A., Komarova Katerina S., Sadovnikov Sergey V., Rustam Matniyazov, Sofronova Alina A., Malyshev Alexander S., Machulkin Alexey E., Petrov Rostislav A., Dmitrii Lukianov, Svetlana Iarovenko, Bezrukov Dmitry S., Baymiev Andrey Kh, Dontsova Olga A.
Журнал: Journal of Antibiotics
Том: 72
Год издания: 2019
Издательство: Japan Antibiotics Research Association/Nihon Koseibusshitsu Gakujutsu Kyogikai
Местоположение издательства: Japan
Первая страница: 827
Последняя страница: 833
DOI: 10.1038/s41429-019-0211-y
Аннотация: 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.
Добавил в систему: Мачулкин Алексей Эдуардович

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