Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Oct;40(10):2363–2368. doi: 10.1128/aac.40.10.2363

Structure-activity relationships of quinolone agents against mycobacteria: effect of structural modifications at the 8 position.

T E Renau 1, J W Gage 1, J A Dever 1, G E Roland 1, E T Joannides 1, M A Shapiro 1, J P Sanchez 1, S J Gracheck 1, J M Domagala 1, M R Jacobs 1, R C Reynolds 1
PMCID: PMC163535  PMID: 8891145

Abstract

A series of quinolones with substitutions at the 8 position has been prepared as part of a study to examine the relationship between structural modifications at this position and activity against mycobacteria. The compounds were prepared by procedures described in the literature and were evaluated for their activities against Mycobacterium fortuitum and Mycobacterium smegmatis. The activities of the compounds against these two organisms were used as a measure of Mycobacterium tuberculosis activity. The results demonstrate that the contribution of the 8 position to antimycobacterial activity was dependent on the substituent at N-1 and was in the order (i) COMe approximately CBr > CCI > CH approximately CF approximately COEt > N > CCF3 when N-1 was cyclopropyl; (ii) N approximately CH > CF > COMe when N-1 was 2,4-difluorophenyl; (iii) N > or = CH when N-1 was tert-butyl; and (iv) N > CH when N-1 was ethyl. In general, derivatives with piperazine substitutions at C-7 were slightly less active against mycobacteria than the analogs with pyrrolidine substitutions, regardless of the pattern of substitution at the 8 position. Several of the best compounds were evaluated for their potential side effects as well as their activities against Mycobacterium aurum, Mycobacterium avium-M. intracellulare, and M. tuberculosis. These agents exhibited biological profiles similar to or better than those of the positive controls ciprofloxacin and sparfloxacin.

Full Text

The Full Text of this article is available as a PDF (207.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bloch A. B., Cauthen G. M., Onorato I. M., Dansbury K. G., Kelly G. D., Driver C. R., Snider D. E., Jr Nationwide survey of drug-resistant tuberculosis in the United States. JAMA. 1994 Mar 2;271(9):665–671. [PubMed] [Google Scholar]
  2. Bouzard D., Di Cesare P., Essiz M., Jacquet J. P., Kiechel J. R., Remuzon P., Weber A., Oki T., Masuyoshi M., Kessler R. E. Fluoronaphthyridines and quinolones as antibacterial agents. 2. Synthesis and structure-activity relationships of new 1-tert-butyl 7-substituted derivatives. J Med Chem. 1990 May;33(5):1344–1352. doi: 10.1021/jm00167a010. [DOI] [PubMed] [Google Scholar]
  3. Bouzard D., Di Cesare P., Essiz M., Jacquet J. P., Remuzon P., Weber A., Oki T., Masuyoshi M. Fluoronaphthyridines and quinolones as antibacterial agents. 1. Synthesis and structure-activity relationships of new 1-substituted derivatives. J Med Chem. 1989 Mar;32(3):537–542. doi: 10.1021/jm00123a005. [DOI] [PubMed] [Google Scholar]
  4. Chu D. T., Fernandes P. B., Maleczka R. E., Jr, Nordeen C. W., Pernet A. G. Synthesis and structure-activity relationship of 1-aryl-6,8-difluoroquinolone antibacterial agents. J Med Chem. 1987 Mar;30(3):504–509. doi: 10.1021/jm00386a011. [DOI] [PubMed] [Google Scholar]
  5. Chung G. A., Aktar Z., Jackson S., Duncan K. High-throughput screen for detecting antimycobacterial agents. Antimicrob Agents Chemother. 1995 Oct;39(10):2235–2238. doi: 10.1128/aac.39.10.2235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen M. A., Griffin T. J., Bien P. A., Heifetz C. L., Domagala J. M. In vitro activity of CI-934, a quinolone carboxylic acid active against gram-positive and -negative bacteria. Antimicrob Agents Chemother. 1985 Dec;28(6):766–772. doi: 10.1128/aac.28.6.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Domagala J. M., Bridges A. J., Culbertson T. P., Gambino L., Hagen S. E., Karrick G., Porter K., Sanchez J. P., Sesnie J. A., Spense F. G. Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship. J Med Chem. 1991 Mar;34(3):1142–1154. doi: 10.1021/jm00107a039. [DOI] [PubMed] [Google Scholar]
  8. Domagala J. M. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother. 1994 Apr;33(4):685–706. doi: 10.1093/jac/33.4.685. [DOI] [PubMed] [Google Scholar]
  9. Drlica K., Xu C., Wang J. Y., Burger R. M., Malik M. Fluoroquinolone action in mycobacteria: similarity with effects in Escherichia coli and detection by cell lysate viscosity. Antimicrob Agents Chemother. 1996 Jul;40(7):1594–1599. doi: 10.1128/aac.40.7.1594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Egawa H., Miyamoto T., Minamida A., Nishimura Y., Okada H., Uno H., Matsumoto J. Pyridonecarboxylic acids as antibacterial agents. 4. Synthesis and antibacterial activity of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and its analogues. J Med Chem. 1984 Dec;27(12):1543–1548. doi: 10.1021/jm00378a004. [DOI] [PubMed] [Google Scholar]
  11. Jacobs R. F. Multiple-drug-resistant tuberculosis. Clin Infect Dis. 1994 Jul;19(1):1–10. doi: 10.1093/clinids/19.1.1. [DOI] [PubMed] [Google Scholar]
  12. Klopman G., Wang S., Jacobs M. R., Bajaksouzian S., Edmonds K., Ellner J. J. Anti-Mycobacterium avium activity of quinolones: in vitro activities. Antimicrob Agents Chemother. 1993 Sep;37(9):1799–1806. doi: 10.1128/aac.37.9.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Matsumoto J., Miyamoto T., Minamida A., Nishimura Y., Egawa H., Nishimura H. Pyridonecarboxylic acids as antibacterial agents. 2. Synthesis and structure-activity relationships of 1,6,7-trisubstituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids, including enoxacin, a new antibacterial agent. J Med Chem. 1984 Mar;27(3):292–301. doi: 10.1021/jm00369a011. [DOI] [PubMed] [Google Scholar]
  14. Nakashima M., Uematsu T., Kosuge K., Kusajima H., Ooie T., Masuda Y., Ishida R., Uchida H. Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans. Antimicrob Agents Chemother. 1995 Dec;39(12):2635–2640. doi: 10.1128/aac.39.12.2635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Narita H., Konishi Y., Nitta J., Kitayama I., Miyazima M., Watanabe Y., Yotsuji A., Saikawa I. [Pyridonecarboxylic acids as antibacterial agents. V. Synthesis and structure-activity relationship of 7-amino-6-fluoro-1-(fluorophenyl)-4-oxo-1,8-naphthyridine-3-carboxylic acids]. Yakugaku Zasshi. 1986 Sep;106(9):802–807. [PubMed] [Google Scholar]
  16. Renau T. E., Sanchez J. P., Gage J. W., Dever J. A., Shapiro M. A., Gracheck S. J., Domagala J. M. Structure-activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes at N-1 and C-7. J Med Chem. 1996 Feb 2;39(3):729–735. doi: 10.1021/jm9507082. [DOI] [PubMed] [Google Scholar]
  17. Renau T. E., Sanchez J. P., Shapiro M. A., Dever J. A., Gracheck S. J., Domagala J. M. Effect of lipophilicity at N-1 on activity of fluoroquinolones against mycobacteria. J Med Chem. 1995 Jul 21;38(15):2974–2977. doi: 10.1021/jm00015a021. [DOI] [PubMed] [Google Scholar]
  18. Sanchez J. P., Bridges A. J., Bucsh R., Domagala J. M., Gogliotti R. D., Hagen S. E., Heifetz C. L., Joannides E. T., Sesnie J. C., Shapiro M. A. New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk. J Med Chem. 1992 Jan 24;35(2):361–367. doi: 10.1021/jm00080a023. [DOI] [PubMed] [Google Scholar]
  19. Sanchez J. P., Domagala J. M., Hagen S. E., Heifetz C. L., Hutt M. P., Nichols J. B., Trehan A. K. Quinolone antibacterial agents. Synthesis and structure-activity relationships of 8-substituted quinoline-3-carboxylic acids and 1,8-naphthyridine-3-carboxylic acids. J Med Chem. 1988 May;31(5):983–991. doi: 10.1021/jm00400a016. [DOI] [PubMed] [Google Scholar]
  20. Sanchez J. P., Gogliotti R. D., Domagala J. M., Gracheck S. J., Huband M. D., Sesnie J. A., Cohen M. A., Shapiro M. A. The synthesis, structure-activity, and structure-side effect relationships of a series of 8-alkoxy- and 5-amino-8-alkoxyquinolone antibacterial agents. J Med Chem. 1995 Oct 27;38(22):4478–4487. doi: 10.1021/jm00022a013. [DOI] [PubMed] [Google Scholar]
  21. Suto M. J., Domagala J. M., Roland G. E., Mailloux G. B., Cohen M. A. Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity. J Med Chem. 1992 Dec 11;35(25):4745–4750. doi: 10.1021/jm00103a013. [DOI] [PubMed] [Google Scholar]
  22. Tomioka H., Saito H., Sato K. Comparative antimycobacterial activities of the newly synthesized quinolone AM-1155, sparfloxacin, and ofloxacin. Antimicrob Agents Chemother. 1993 Jun;37(6):1259–1263. doi: 10.1128/aac.37.6.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Weltman A. C., Rose D. N. Tuberculosis susceptibility patterns, predictors of multidrug resistance, and implications for initial therapeutic regimens at a New York City hospital. Arch Intern Med. 1994 Oct 10;154(19):2161–2167. [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES