Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity.

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Jean-Philippe Surivet, Roland Lange, Christian Hubschwerlen, Wolfgang Keck, Jean-Luc Specklin, Daniel Ritz, Daniel Bur, Hans Locher, Peter Seiler, Daniel Stefan Strasser, Lars Prade, Christopher Kohl, Christine Schmitt, Gaëlle Chapoux, Eser Ilhan, Nadia Ekambaram, Alcibiade Athanasiou, Andreja Knezevic, Daniela Sabato, Alain Chambovey, Mika Gaertner, Michel Enderlin, Maria Boehme, Virginie Sippel, Pierre Wyss. Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity. Bioorganic & medicinal chemistry letters. 2012 Nov 1;22(21):6705-11

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PMID: 23006603

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