title: Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity.
abstract: A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. jean-philippe.surivet@actelion.com
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Surivet
authors.forename: Roland
authors.initials: R
authors.lastname: Lange
authors.forename: Christian
authors.initials: C
authors.lastname: Hubschwerlen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Keck
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Specklin
authors.forename: Daniel
authors.initials: D
authors.lastname: Ritz
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Hans
authors.initials: H
authors.lastname: Locher
authors.forename: Peter
authors.initials: P
authors.lastname: Seiler
authors.forename: Daniel Stefan
authors.initials: DS
authors.lastname: Strasser
authors.forename: Lars
authors.initials: L
authors.lastname: Prade
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: Christine
authors.initials: C
authors.lastname: Schmitt
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Chapoux
authors.forename: Eser
authors.initials: E
authors.lastname: Ilhan
authors.forename: Nadia
authors.initials: N
authors.lastname: Ekambaram
authors.forename: Alcibiade
authors.initials: A
authors.lastname: Athanasiou
authors.forename: Andreja
authors.initials: A
authors.lastname: Knezevic
authors.forename: Daniela
authors.initials: D
authors.lastname: Sabato
authors.forename: Alain
authors.initials: A
authors.lastname: Chambovey
authors.forename: Mika
authors.initials: M
authors.lastname: Gaertner
authors.forename: Michel
authors.initials: M
authors.lastname: Enderlin
authors.forename: Maria
authors.initials: M
authors.lastname: Boehme
authors.forename: Virginie
authors.initials: V
authors.lastname: Sippel
authors.forename: Pierre
authors.initials: P
authors.lastname: Wyss
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D011088:DNA Ligases / Q000037:antagonists & inhibitors*; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors; D015195:Drug Design; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D011088:DNA Ligases