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

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 18, 2009, Pages 5355-5358

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

^a Affinium Pharmaceuticals Inc   (Canada)

Author keywords

Enoyl ACP reductase; Naphthyridinone

Indexed keywords

ENOYL ACYL CARRIER PROTEIN REDUCTASE (NADH); ENZYME INHIBITOR; NAPHTHYRIDINE DERIVATIVE; PIPERIDINE DERIVATIVE; PROTEIN FABI; SPIRO COMPOUND; UNCLASSIFIED DRUG;

ARTICLE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; ESCHERICHIA COLI; IC 50; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; REACTION ANALYSIS; STAPHYLOCOCCUS AUREUS; STRUCTURE ANALYSIS;

ANTI-BACTERIAL AGENTS; CATALYTIC DOMAIN; ENOYL-(ACYL-CARRIER-PROTEIN) REDUCTASE (NADH); ESCHERICHIA COLI; MODELS, MOLECULAR; NAPHTHYRIDINES; PIPERIDINES; PROTEIN BINDING; SPIRO COMPOUNDS; STAPHYLOCOCCUS AUREUS; STRUCTURE-ACTIVITY RELATIONSHIP;

ESCHERICHIA COLI; STAPHYLOCOCCUS AUREUS;

EID: 68949101821     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.129     Document Type: Article

References (15)

1. Chu D.T.W., Plattner J.J., and Katz L. J. Med. Chem. 39 (1996) 3853
2. Projan S.J. Curr. Opin. Pharmacol. 2 (2002) 513
3. White S.W., Zheng J., Zhang Y., and Rock C.O. Annu. Rev. Biochem. 74 (2005) 791
4. Heerding D.A., Chan G., DeWolf W.E., Fosberry A.P., Janson C.A., Jaworski D.D., McManus E., Miller W.H., Moore T.D., Payne D.J., Qiu X., Rittenhouse S.F., Slater-Radosti C., Smith W., Takata D.T., Vaidya K.S., Yuan C.C.K., and Huffman W.F. Bioorg. Med. Chem. Lett. 11 (2001) 2061
5. Miller W.H., Seefeld M.A., Newlander K.A., Uzinskas I.N., Burgess W.J., Heerding D.A., Yuan C.C.K., Head M.S., Payne D.J., Rittenhouse S.F., Moore T.D., Pearson S.C., Berry V., DeWolf W.E., Polizzi B.J., Qiu X., and Janson C.A. J. Med. Chem. 45 (2002) 3246
6. Seefeld M.A., Miller W.H., Newlander K.A., Burgess W.J., DeWolf W.E., Elkins P.A., Head M.S., Jakas D.R., Janson C.A., Keller P.M., Manley P.J., Heerding D.A., Chan G., Fosberry A.P., Jaworski D.D., Moore T.D., Payne D.J., Pearson S., Polizzi B.J., Qiu X., Rittenhouse S.F., Uzinskas I.N., Wallis N.G., and Huffman W.F. J. Med. Chem. 46 (2003) 1627
7. Lu H., and Tonge P.J. Acc. Chem. Res. 41 (2008) 11
8. Moir D.T. Curr. Drug Targets Infect. Disord. 5 (2005) 297
9. Brinster S., Lamberet G., Stael B., Trieu-Cuot P., Gruss A., and Poyart C. Nature 458 (2009) 83
10. The coordinates were obtained from the PBD under the accession code 1MFP.
11. Berman, J; Sampson, P.; Pauls, H.W.; Ramnauth, J.; Manning, D.; Surman, M.D.; Xie, D.; Decornez, H.Y.; Pct. Intl. Appl. WO 2004052890, 2004.
12. Clarke, T.; Buzadzja, K.; Dorsey, M.; Abstract of papers, 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, October, 2004; Abstract F-1527.
13. Cignarella G., Villa S., and Barlocco D. Eur. J. Med. Chem. 29 (1994) 115
14. S. aureus FabI inhibition assays were carried out as described in Ref. 5, using a FabI enzyme concentration of 3 nM. E. coli FabI inhibition assays were carried out in half area 96 well plates containing 150 μL of 100 mM MOPS pH 7.2, 50 mM ammonium acetate, 3% glycerol, 25 μM crotonyl-ACP, 50 μM NADH, and 0.5 nM enzyme. Consumption of NAD(P)H was monitored at 340 nm and a titration of standard compound was included on each dose response plate as a positive control.
15. MIC testing was performed on bacterial strains from the Affinium bacterial collection or the American Type Culture Collection (Manassas, VA) according to CLSI guidelines using the microdilution method in 96 wellplates: National Committee for Clinical Laboratory Standards 2003. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, Fifth Ed., Approved Standard M7-A6. NCCLS, Wayne, PA, USA.