Antibacterial activity of noscapine analogs

Yan A. Ivanenkov, Kseniya Yu. Filyaeva, Rustam T. Matniyazov, Andrey Kh Baymiev, Alexey Kh Baymiev, Anastasiya A. Vladimirova, Renat S. Yamidanov, Ayrat R. Mavzyutov, Zulfia R. Zileeva, Liana F. Zainullina, Julia V. Vakhitova, Valeriya I. Marina, Victor A. Terentiev, Ilya A. Osterman, Victor G. Kartsev, Dmitry S. Bezrukov, Olga A. Dontsova

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The antibacterial properties of close noscapine analogs have not been previously reported. We used our pDualrep2 double-reporter High Throughput Screening (HTS) platform to identify a series of noscapine derivatives with promising antibacterial activity. The platform is based on RPF (SOS-response/DNA damage) and Katushka2S (inhibition of translation) proteins and simultaneously provides information on antibacterial activity and the mechanism of action of small-molecule compounds against E. coli. The most potent compound exhibited an MIC of 13.5 µM (6.25 µg/ml) and a relatively low cytotoxicity against HEK293 cells (CC50 = 71 µM, selectivity index: ~5.5). Some compounds from this series induced average Katushka2S reporter signals, indicating inhibition of translation machinery in the bacteria; however, these compounds did not attenuate translation in vitro in a luciferase-based translation assay. The most effective compounds did not significantly arrest the mitotic cycle in HEK293 cells, in contrast to the parent compound in a flow cytometry assay. Several molecules showed activity against clinically relevant gram-negative and gram-positive bacterial strains. Compounds from the discovered series can be reasonably regarded as good templates for further development and evaluation.

Original languageEnglish
Article number128055
JournalBioorganic and Medicinal Chemistry Letters
Volume43
DOIs
Publication statusPublished - 1 Jul 2021

Keywords

  • Antibacterial activity
  • HTS
  • Noscapine
  • Screening
  • SOS-response
  • Translation inhibitors

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