Archives of Pharmacal Research

, Volume 33, Issue 6, pp 831–842 | Cite as

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Research Articles Drug Design


Two series of novel 2-butyl succinate-based Hydroxamate derivatives containing isoxazole rings were synthesized, characterized and evaluated for antibacterial activity. The synthesized compounds were found to exhibit weak to moderate inhibitory activity against Staphytlococcusaureu and Klebsiellar pneumonia in vitro. All the compounds synthesized were found to be more effective against Klebsiellar pneumonia compared to Staphytlococcus aureu.

Key words

2-Butyl succinate-based hydroxamate derivatives Isoxazole Synthesis Antibacterial activity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aarons, S. J., Sutherland, I. W., Chakrabarty, A. M., and Gallagher, M. P., A novel gene, algK, from the alginate biosynthetic cluster of Pseudomonas aeruginosa. Microbiology, 143, 641–652 (1997).CrossRefPubMedGoogle Scholar
  2. Broughton, B. J., Chaplen, P., Freeman, W. A., Warren, P. J., Wooldridge, K. R. H., and Wright, D. E., Studies concerning the antibiotic actinonin. Part VIII. Structureactivity relationships in the actinonin series. J. Chem. Soc. Perkin Trans. I, 857–860 (1975).CrossRefGoogle Scholar
  3. Chen, D. Z., Patel, D. V., Hackbarth, C. J., Wang, W., Dreyer, G., Young, D. C., Margolis, P. S., Wu, C., Ni, Z., Trias, J., White, R. J., and Yuan, Z., Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry, 39, 1256–1262 (2000).CrossRefPubMedGoogle Scholar
  4. Chen, D., Hackbarth, C., Ni, Z. J., Wu, C., Wang, W., Jain, R., He, Y., Bracken, K., Weidmann, B., Patel, D. V., Trias, J., White, R. J., and Yuan, Z., Peptide deformylase inhibitors as antibacterial agents: Identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach. Antimicrob. Agents Chemother., 48, 250–261 (2004).CrossRefPubMedGoogle Scholar
  5. Chu, M., Mierzwa, R., He, L., Xu, L., Gentile, F., Terracciano, J., Patel, M., Miesel, L., Bohanon, S., Kravec, C., Cramer, C., Fischman, T. O., Hruza, A., Ramanathan, L., Shipkova, P., and Chan, T., Isolation and structure elucidation of two novel deformylase inhibitors produced by Streptomyces sp. Tetrahedron Lett., 42, 3549–3551 (2001).CrossRefGoogle Scholar
  6. Chung, Y. J., Kim, D., Choi, K. Y., Kim, B. H., Synthesis and inhibitory activities of HIV-1 protease inhibitors containing 2-isoxazoline derivatives. Korean J. Med. Chem., 5, 141–161 (1995).Google Scholar
  7. Clements, J. M., Beckett, P., Brown, A., Catlin, G., Lobell, M., Palan, S., Thomas, W., Whittaker, M., Baker, P. J., Rodgers, F., Barynin, V., Rice, D. W., Hunter, M. G., Antibiotic Activity and Characterization of BB-3497, a Novel Peptide Deformylase Inhibitor. Antimicrob. Agents Chemother., 45, 563–570 (2001).CrossRefPubMedGoogle Scholar
  8. Davies, J., Inactivation of antibiotics and the dissemination of resistance genes. Science, 264, 375–382 (1994).CrossRefPubMedGoogle Scholar
  9. East, S. P., Beckett, R. P., Brookings, D. C., Clements, J. M., Doel, S., Keavey, K., Pain, G., Smith, H. K., Thomas, W., Thompson, A. J., Todd, R. S., and Whittaker, M., Peptide deformylase inhibitors with activity against respiratory tract pathogens. Bioorg. Med. Chem. Lett., 14, 59–62 (2004).CrossRefPubMedGoogle Scholar
  10. Giglione, C., Serero, A., and Pierre, M., Identification of eukaryotic peptide deformylases reveals universality of Nterminal protein processing mechanisms. EMBO J., 19, 5916–5929 (2000).CrossRefPubMedGoogle Scholar
  11. Guilloteau, J., Mathieu, M., Giglione, C., Blanc, V., Dupuy, A., Chevrier, M., Gil, P., Famechon, A., Meinnel, T., and Miko, V., The Crystal Structures of Four Peptide Deformylases Bound to the Antibiotic Actinonin Reveal Two Distinct Types: A Platform for the Structure-based Design of Antibacterial Agents. J. Mol. Biol., 320, 951–962 (2002).CrossRefPubMedGoogle Scholar
  12. Ho, C. Y., Strobel, E., Ralbovsky, J., and Galemmo. R. A., Improved solution- and solid-phase preparation of hydroxamic acids from esters. J. Org. Chem., 70, 4873–4875 (2005).CrossRefPubMedGoogle Scholar
  13. Jain, R., Chen, D., White, R. J., Patel, D. V., and Yuan, Z., Bacterial peptide deformylase inhibitors: A new class of antibacterial agents. Curr. Med. Chem., 12, 1607–1621 (2005).CrossRefPubMedGoogle Scholar
  14. Kamiski, Z. J., 2-Chloro-4,6-dimethoxy-1,3,5-triazine. A new coupling reagent for peptide synthesis. Synthesis, 1987, 917–920 (1987).CrossRefGoogle Scholar
  15. Koneman, E. W., Allen, S. D., and Winn, W. C., Color atlas and textbook of diagnostic microbiology. Lippincott Raven Pub, Philadelphia, pp. 86–856, (1997).Google Scholar
  16. Lee, M. D., She, Y., Soskis, M. J., Borella, C. P., Gardner, J. R., Hayes, P.A., Dy, B. M., Heaney, M. L., Philips, M. R., Bornmann, W. G., Sirotnak, F. M., and Scheinberg, D. A., Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics. J. Clin. Invest., 114, 1107–1116 (2004).PubMedGoogle Scholar
  17. Levy, D. E., Lapierre, F., Liang, W., Ye, W., Lange, C. W., Li, X., Grobelny, D., Terrell, M., Holme, K., Nadzan, A., and Galardy, R. E., Matrix Metalloproteinase Inhibitors: A StructureActivity Study. J. Med. Chem., 41, 199–223 (1998).CrossRefPubMedGoogle Scholar
  18. Lofland, D., Difuntorum, S., Waller, A., Clements, J. M., Weaver, M. K., Karlowsky, J. A., and Johnson, K., In vitro antibacterial activity of the peptide deformylase inhibitor BB-83698. J. Antimicrob. Chemother., 53, 664–668 (2004).CrossRefPubMedGoogle Scholar
  19. Madison, V., Duca, J., Bennett, F., Bohanon, S., Cooper, A., Chu, M., Desai, J., Girijavallabhan, V., Hare, R., Hruza, A., Hendrata, S., Huang, Y., Kravec, C., Malcolm, B., McCormick, J., Miesel, L., Ramanathan, L., Reichert, P., Saksena, A., Wang, J., Weber, P. C., Zhu, H., and Fischmann, T., Binding affinities and geometries of various metal ligands in peptide deformylase inhibitors. Biophys. Chem., 101–102, 239–247 (2002).CrossRefPubMedGoogle Scholar
  20. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard, Sixth Edition; NCCLS documents M7-A6. National Committee for Clinical Laboratory Standards, Wayne, Pa, (2003).Google Scholar
  21. Penning, T. D., Khilevich, A., Chen, B. B., Russell, M. A., Boys, M. L., Wang, Y., Duffin, T., Engleman, V. W., Finn, M. B., Freeman, S. K., Hanneke, M. L., Keene, J. L., Klover, J. A., Nickols, G. A., Nickols, M.A., Rader, R. K., Settle, S. L., Shannon, K. E., Steininger, C. N., Westlinc, M. M., and Westlin, W. F., Synthesis of pyrazoles and isoxazoles as potent αvβ3 receptor antagonists. Bioorg. Med. Chem. Lett., 16, 3156–3161 (2006).CrossRefPubMedGoogle Scholar
  22. Reddy, A. S., Kumar, M. S., and Reddy, G. R., A convenient method for the preparation of hydroxamic acids. Tetrahedron Lett., 41, 6285–6288 (2000).CrossRefGoogle Scholar
  23. Shen, G., Zhu, J., Simpson, A. M., and Pei, D., Design and synthesis of macrocyclic peptidyl hydroxamates as peptide deformylase inhibitors. Bioorg. Med. Chem. Lett., 18, 3060–3063 (2008).CrossRefPubMedGoogle Scholar
  24. Smith, H. K., Beckett, R. P., Clements, J. M., Doel, S., East, S. P., Launchbury, S. B., Pratt, L. M., Spavold, Z. M., Thomas, W., Todd, R. S., and Whittaker, M., Structureactivity relationships of the peptide deformylase inhibitor BB-3497: modification of the metal binding group. Bioorg. Med. Chem. Lett., 12, 3595–3599 (2002).CrossRefPubMedGoogle Scholar
  25. Spratt, B. G., Resistance to antibiotics mediated by target alterations BG Spratt. Science, 264, 388–393 (1994).CrossRefPubMedGoogle Scholar
  26. Yuan, Z., Trias, J., and White, R. J., Deformylase as a novel antibacterial target. Drug Discov. Today, 6, 954–961 (2001).CrossRefPubMedGoogle Scholar
  27. Zhang, D. T., Tang, L. D., Duan, G. Y., Zhao, G. L., Xu, W. R., Meng, L. J., and Wang. J. W., Synthesis, resolution, and enantiomeric purity assay of 2-n-butylbutanedioic acid 4-t-butyl esters. Chem. Res. Chin. Univ., 22, 584–588 (2006).CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2010

Authors and Affiliations

  1. 1.School of Chemistry and Chemical EngineeringShandong UniversityJinan, ShandongChina
  2. 2.School of Chemical EngineeringShandong Institute of Light IndustryJinan, ShandongChina
  3. 3.Tianjin Key Laboratory of Molecular Design and Drug DiscoveryTianjin Institute of Pharmaceutical ResearchTianjinChina

Personalised recommendations