Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform

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.; Chemeris, A.V.; Baimiev, A.K.; Sofronova, A.A.; Malyshev, A.S.; Machulkin, A.E.; Petrov, R.A.; Bezrukov, D.S.; Filkov, G.I.; Puchinina, M.M.; Zainullina, L.F.; Maximova, M.A.; Zileeva, Z.R.; Vakhitova, Y.V.; 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., Chemeris Alexey V., Baimiev Alexey Kh, Sofronova Alina A., Malyshev Alexander S., Machulkin Alexey E., Petrov Rostislav A., Bezrukov Dmitry S., Filkov Gleb I., Puchinina Maria M., Zainullina Liana F., Maximova Marina A., Zileeva Zulfiya R., Vakhitova Yulia V., Dontsova Olga A.
Журнал: Combinatorial Chemistry and High Throughput Screening
Том: 22
Номер: 5
Год издания: 2019
Издательство: Bentham Science Publishers
Местоположение издательства: Netherlands
Первая страница: 346
Последняя страница: 354
DOI: 10.2174/1386207322666190412165316
Аннотация: Aim and Objective: Antibiotic resistance is a serious constraint to development of the new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity. Materials and Methods: Using our unique double-reporter system, in-house large-scale HTS campaign was conducted for identification of antibacterial potency of small-molecule compounds. The construction allows us to visually assess the underlying mechanism of action. After the initial HTS and rescreen procedure, luciferase assay, C14-test, determination of MIC value and PrestoBlue test were carried out. Results: HTS rounds and rescreen campaign have revealed the antibacterial activity of a series of N-substituted triazolo-azetidines and their isosteric derivatives that has not been reported previously. Primary hit-molecule demonstrated a MIC value of 12.5 µg/mL against E. coli tolC with signs of translation blockage and no SOS-response. Translation inhibition (26%, luciferase assay) was achieved at high concentrations up to 160 µg/mL, while no activity was found using C14-test. The compound did not demonstrate cytotoxicity in the PrestoBlue assay against a panel of eukaryotic cells. Within a series of direct structural analogues bearing the same or bioisosteric scaffold, compound 2 was found to have an improved antibacterial potency (MIC=6.25 µg/mL) close to Erythromycin (MIC=2.5-5 µg/mL) against the same strain. In contrast to the parent hit, this compound was more active and selective, and provided a robust IP position. Conclusion: N-substituted triazolo-azetidine scaffold may be used as a versatile starting point for the development of novel active and selective antibacterial compounds.
Добавил в систему: Мачулкин Алексей Эдуардович

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Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platformстатья