title: Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: structure based design, synthesis, SAR and antimicrobial activity.
abstract: The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Yule
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Woodstock Road, Begbroke, Oxfordshire OX5 1PF, UK.
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Czaplewski
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Woodstock Road, Begbroke, Oxfordshire OX5 1PF, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pommier
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Woodstock Road, Begbroke, Oxfordshire OX5 1PF, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Davies
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Narramore
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK. Electronic address: C.W.G.Fishwick@leeds.ac.uk.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D014508:Urea; D027081:DNA Gyrase
keywords: Bacterial resistance; DNA gyrase; Molecular modelling; Pyridine-3-carboxamide