New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase

Sarah Narramore; Clare E M Stevenson; Anthony Maxwell; David M Lawson; Colin W G Fishwick

doi:10.1016/j.bmc.2019.06.015

New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase

Bioorg Med Chem. 2019 Aug 15;27(16):3546-3550. doi: 10.1016/j.bmc.2019.06.015. Epub 2019 Jun 14.

Authors

Sarah Narramore¹, Clare E M Stevenson², Anthony Maxwell², David M Lawson², Colin W G Fishwick³

Affiliations

¹ School of Chemistry and the Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
² Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
³ School of Chemistry and the Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: c.w.g.fishwick@leeds.ac.uk.

PMID: 31257079
DOI: 10.1016/j.bmc.2019.06.015

Abstract

Previously we have reported on a series of pyridine-3-carboxamide inhibitors of DNA gyrase and DNA topoisomerase IV that were designed using a computational de novo design approach and which showed promising antibacterial properties. Herein we describe the synthesis of additional examples from this series aimed specifically at DNA gyrase, along with crystal structures confirming the predicted mode of binding and in vitro ADME data which describe the drug-likeness of these compounds.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Gyrase / genetics*
Escherichia coli / metabolism*
Models, Molecular
Structure-Activity Relationship
Topoisomerase II Inhibitors / pharmacology
Topoisomerase II Inhibitors / therapeutic use*

Substances

Topoisomerase II Inhibitors
DNA Gyrase

Grants and funding

BBS/E/J/00000201/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom