The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 8, 2007, Pages 2150-2155

  Murphy, Sean T ^a   Case, Heather L ^a   Ellsworth, Edmund ^a   Hagen, Susan ^a   Huband, Michael ^a   Joannides, Themis ^a   Limberakis, Chris ^a   Marotti, Keith R ^a   Ottolini, Amy M ^a   Rauckhorst, Mark ^a   Starr, Jeremy ^a   Stier, Michael ^a   Taylor, Clarke ^a   Zhu, Tong ^a   Blaser, Adrian ^b   Denny, William A ^b   Lu, Guo Liang ^b   Smaill, Jeff B ^b   Rivault, Freddy ^c  

^a PFIZER INC   (United States)

^b UNIVERSITY OF AUCKLAND   (New Zealand)

^c UMR7175   (France)

Author keywords

Antibacterial; Dofetilide; Fluoroquinolones; hERG; Nitriles; PF 02298732; PF 00951966; PF 02789402; pKa; Resistance

Indexed keywords

AMINE; AZETIDINE; CIPROFLOXACIN; DOFETILIDE; LEVOFLOXACIN; NITRILE; PF 00951966; PF 02298732; POTASSIUM CHANNEL HERG; QUINOLINE DERIVED ANTIINFECTIVE AGENT; UNCLASSIFIED DRUG;

ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL STRAIN; BIOLOGICAL ACTIVITY; CLONOGENESIS; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DETERMINATION; DRUG INHIBITION; DRUG SAFETY; DRUG SCREENING; DRUG SYNTHESIS; GENOTOXICITY; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HUMAN; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; NONHUMAN; STREPTOCOCCUS PNEUMONIAE;

ANIMALS; ANTI-BACTERIAL AGENTS; DRUG RESISTANCE, BACTERIAL; FLUOROQUINOLONES; GRAM-NEGATIVE BACTERIA; GRAM-POSITIVE BACTERIA; HUMANS; MOLECULAR STRUCTURE; MUTAGENICITY TESTS; NITRILES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; NEGIBACTERIA; POSIBACTERIA; RATTUS; STREPTOCOCCUS PNEUMONIAE;

EID: 33947731626     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.01.090     Document Type: Article

References (21)

1. Talbot G.H., Bradley J., Edwards Jr. J.E., Gilbert D., Scheld M., and Bartlett J.G. Clin. Infect. Dis. 42 (2006) 657
2. Theuretzbacher U., and Toney J.H. Curr. Opin. Investig. Drugs 7 (2006) 158
3. Bakkan J.S. Scand. J. Infect. Dis. 36 (2004) 85
4. Kang J., Wang L., Chen X.-L., Triggle D.J., and Rampe D. Mol. Pharmacol. 59 (2001) 122
5. Owens Jr. R.C. Drugs 64 (2004) 1091
6. Jalaie M., and Holsworth D.D. Mini-Rev. Med. Chem. 5 (2005) 1083
7. Domagala J.M., Hagen S.E., Joannides T., Keily J.S., Laborde E., Schroeder M.C., Seanie J.A., Shapiro M.A., Suto M.J., and Vanderroest S. J. Med. Chem. 36 (1993) 871
8. Suto M.J., Domagala J.M., Roland G.E., Mailloux G.B., and Cohen M.A. J. Med. Chem. 35 (1992) 4745
9. Jones M.E., Critchley I.A., Karlowsky J.A., Blosser-Middleton R.S., Schmitz F.-J., Thornsberry C., and Sahm D.F. Antimicrob. Agents Chemother. 46 (2002) 1651
10. Yoshiyasu T., Hiromi K., Nobuyuki I., and Kazuo A. Chem. Pharm. Bull. 33 (1985) 2762
11. R MICs for stereoisomers of 22: diastereomer A (faster eluting) = 8 μg/mL, diastereomer B (slower eluting) = 1 μg/mL, and enantiomer B1 (faster eluting) = 8 μg/mL, enantiomer B2 (slower eluting, desired) = 0.5 μg/mL. Diastereomers were separated on silica gel eluted with hexanes/ethyl acetate. Enantiomers were separated by chiral HPLC on a ChiralPak AD column eluted with methanol/ethanol.
12. Baldwin J.E., Adlington R.M., and Gollins D.W. Tetrahedron 51 (1995) 5169
13. Frigola J., Pares J., Corbera J., Vano D., Merce R., Torrens A., Mas J., and Valenti E. J. Med. Chem. 36 (1993) 801
14. Denmark S.E., Forbes D.C., Hays D.S., DePue J.S., and Wilde R.G. J. Org. Chem. 60 (1995) 1391
15. 50 for compound 22 against Escherichia coli strains and ESBL producing strains of Klebsiella pneumoniae is 32 μg/ml.
16. Compounds in the azetidine series with R = n-propyl, isopropyl, and cyclopropropyl were also active, but did not offer any advantages over R = ethyl (37).
17. 3H]-dofetilide was used as described in: Greengrass, P. M.; Stewart, M.; Wood, C. M. World Patent WO2003021271, 2003.
18. Dofetilide was found to be a useful indicator of hERG activity for our series. Internally, we have demonstrated a correlation between the dofetilide displacement assay and the hERG patch clamp assay for these compounds.
19. Fraley M.E., Arrington K.L., Buser C.A., Ciecko P.A., Coll K.E., Fernandes C., Hartman G.D., Hoffman W.F., Lynch J.L., McFall R.C., Rickert K., Singh R., Smith S., Thomas K.A., and Wong B.K. Bioorg. Med. Chem. Lett. 14 (2004) 351
20. a was measured of the conjugate acid of the most basic group by capillary electrophoresis:. Jia Z., Ramstad T., and Zhong M. Electrophoresis 22 (2001) 1112
21. Gracheck, S. J.; Mychalonka, M.; Gambino, L.; Cohen, M.; Roland, G.; Ciaravino, V.; Worth, D.; Theiss, J. C.; Heifetz, C. 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 1991; Abstract No. 1488.