Spiro-naphthyridinone piperidines as inhibitors of S. aureus and E. coli enoyl-ACP reductase (FabI)

Peter B Sampson; Christine Picard; Sean Handerson; Teresa E McGrath; Megan Domagala; Andrew Leeson; Vladimir Romanov; Donald E Awrey; Dhushy Thambipillai; Elias Bardouniotis; Nachum Kaplan; Judd M Berman; Henry W Pauls

doi:10.1016/j.bmcl.2009.07.129

Spiro-naphthyridinone piperidines as inhibitors of S. aureus and E. coli enoyl-ACP reductase (FabI)

Bioorg Med Chem Lett. 2009 Sep 15;19(18):5355-8. doi: 10.1016/j.bmcl.2009.07.129. Epub 2009 Aug 6.

Authors

Peter B Sampson¹, Christine Picard, Sean Handerson, Teresa E McGrath, Megan Domagala, Andrew Leeson, Vladimir Romanov, Donald E Awrey, Dhushy Thambipillai, Elias Bardouniotis, Nachum Kaplan, Judd M Berman, Henry W Pauls

Affiliation

¹ Affinium Pharmaceuticals Inc. 1243 Islington Ave., Suite 600, Toronto, Ontario, Canada M8X 1Y9. psampson@uhnresearch.ca

PMID: 19682901
DOI: 10.1016/j.bmcl.2009.07.129

Abstract

Spiropiperidine naphthyridinone inhibitors of Staphylococcus aureus and Escherichia coli FabI have been prepared. Compounds 14a and 14c were identified as having sub-nanomolar E. coli FabI activity and are among the most potent FabI inhibitors yet described. The structural model of 14a bound to E. coli FabI is shown.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Catalytic Domain
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / chemistry
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / metabolism*
Escherichia coli / enzymology*
Models, Molecular
Naphthyridines / chemistry
Naphthyridines / pharmacology*
Piperidines / chemistry
Piperidines / pharmacology*
Protein Binding
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Staphylococcus aureus / enzymology*
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Naphthyridines
Piperidines
Spiro Compounds
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)