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Structure-Activity Relationships of Fluoro-4-Quinolones

  • L. A. Mitscher
  • P. V. Devasthale
  • R. M. Zavod
Part of the Springer Series in Applied Biology book series (SSAPPL.BIOLOGY)

Abstract

The quinolone anti-infective field is now more than twenty years old and several thousand agents have been prepared from which to assemble generalizations connecting structure and activity. This is still a somewhat risky activity as this field all too often throws up an analog which does not fit the classic pattern and yet has excellent activity. Successfully rationalizing such a discovery often teaches us more than the addition of several more typical examples. The establishment of an incorrect orthodoxy by over interpretation of evidence inhibits such liberating discovery and narrows the scope of investigation. Nonetheless, a periodic critical examination of the cumulative experience in the field is essential in planning new work. In this review the primary emphasis will be on the fluoroquinolones of greatest contemporary interest and on the analogs which do not fit comfortably with the rest.

Keywords

Anti Bacterial Agent Nalidixic Acid Oxolinic Acid Pipemidic Acid Bioisosteric Replacement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Achari A, Neidle S (1976) Nalidixic acid Acta Cryst B32: 600–602Google Scholar
  2. Albrecht R (1977) Development of antibacterial agents of the nalidixic acid type. Prog Drug Research 21:11–104Google Scholar
  3. Atarashi S, Yokohama S, Yamazaki K, Sakano K, Imamura M, Hayakawa I (1987) Synthesis and antibacterial activities of optically active ofloxacin and its fluoromethyl derivative. Chem Pharm Bull (Japan) 35:1896–1902CrossRefGoogle Scholar
  4. Bouzard D, DiCesare P, Essiz M, Jacquet JP, Remuzon P, Weber A, Oki T, Masuyoshi M (1989) Fluoronaphthyridines and quinolones as antibacterial agents. 1 Synthesis and structure-activity relationships of new 1-substituted derivatives. J Med Chem 32:537–542PubMedCrossRefGoogle Scholar
  5. Cecchetti V, Fravolini A, Fringuelli R, Mascellani G, Pagella P, Palmioli M, Segre G, Terni P (1987) Quinolonecarboxylic acids. 2 Synthesis and antibacterial evaluation of 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [l,4]benzomiazine-6-carboxylic acids. J Med Chem 30:465–473PubMedCrossRefGoogle Scholar
  6. Chu DTW, Fernandes PB, Claiborne AK, Pihuleac E, Nordeen CW, Maleczka RE Jr, Pernet AG (1985) Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents. J Med Chem 28:1558–1564PubMedCrossRefGoogle Scholar
  7. Chu DTW, Fernandes PB, Pernet AG (1986a) Synthesis and biological activity of benzothiazolo [3,2-a]quinolone antibacterial agents. J Med Chem 29:1531–1534PubMedCrossRefGoogle Scholar
  8. Chu DTW, Fernandes PB, Claiborne AK, Gracey EH, Pernet AG (1986b) Synthesis and structure-activity relationships of new arylfluoronaphthyridine antibacterial agents. J Med Chem 29:2363–2369PubMedCrossRefGoogle Scholar
  9. Chu DTW, Fernandes PB, Maleczka RE, Jr, Nordeen CW, Pernet AG (1987) Synthesis and structure-activity relationship of l-aryl-6,8-difluoroquinolone antibacterial agents. J Med Chem 30:504–509PubMedCrossRefGoogle Scholar
  10. Chu DTW, Fernandes PB, Claiborne AK, Shen LL, Pernet AG (1989) Structure-activity relationships in quinolone antibacterials: replacement of the 3-carboxylic acid group In: Fernandes PB (ed) Quinolones. Prous, Barcelona, Spain pp 37–46Google Scholar
  11. Culbertson TP, Domagala JM, Nichols JB, Priebe S, Skeean RW (1987) Enantiomers of l-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid: preparation and biological activity. J Med Chem 30:1711–1715PubMedCrossRefGoogle Scholar
  12. Domagala JM, Hanna LD, Heifetz, CL, Hutt MP, Mich TF, Sanchez JP, Solomon P (1986) New Structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay. J Med Chem 29:394–403PubMedCrossRefGoogle Scholar
  13. Domagala JM, Heifetz CL, Hutt MP, Mich TF, Nichols JB, Solomon M, Worth DF (1988a) 1-Substituted 7-[3[(ethylamino)methyl]-l-pyirolidinyl]-6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acids. New quantitative structure-activity relationships at N-l for the quinolone antibacterials. J Med Chem 31:991–1001PubMedCrossRefGoogle Scholar
  14. Domagala JM, Hagen SE, Heifetz CL, Hutt MP, Mich TF, Sanchez JP, Trehan AK (1988b) 7-Substituted-5-amino-l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acids: Synthesis and biological activity of a new class of quinolone antibacterials. J Med Chem 31:503–506PubMedCrossRefGoogle Scholar
  15. Georgopapadakou NH, Dix BA, Angehem P, Wick A, Olson G (1985) Monocyclic and tricyclic analogs of quinolones: Biological properties. Abstr 25th Intersci Conf Antimicrob Agents Chemother (Minneapolis, MN, 29 Sept-2 Oct) Abstr 129Google Scholar
  16. Gerster JF, Rohlfing SR, Pecore SE, Winandy RM, Stern RM, Landmesser JE, Olsen RA, Gleason WB (1987) Synthesis, absolute configuration, and antibacterial activity of 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. J Med Chem 30:839–843PubMedCrossRefGoogle Scholar
  17. Gerster JF, Rohlfing SR, Rustad NJ, Reiter MJ, Pecore SE, Winandy RM, Landmesser JE (1989) The synthesis and pharmacological profile of the stereoisomers of a tricyclic quinolone antibacterial In: Fernandes PB (ed) Quinolones. Prous Science Publishers, Barcelona, Spain pp 85–98Google Scholar
  18. Hayakawa I, Hiramitsu T, Tanaka Y (1984) Synthesis and antibacterial activities of substituted 7-oxo-2,3-dihydro-7H-pyrido[l,2,3de][l,4]benzoxazine-6-carboxylic acids. Chem Pharm Bull (Japan) 32:4907–4913CrossRefGoogle Scholar
  19. Hogberg T, Vora M, Drake SD, Mitscher LA, Chu DTW (1984a) Structure-activity relationships among DNA-gyrase inhibitors. Synthesis and antimicrobial evaluation of chromones and coumarins related to oxolinic acid. Acta Chem Scand A 38:359–366CrossRefGoogle Scholar
  20. Hogberg T, Khanna I, Drake SD, Mitscher LA, Shen LL (1984b) Structure-activity relationships among DNA gyrase inhibitors. Synthesis and biological evaluation of 1,2-dihydro-4,4-dimethyl-1-oxo-2-naphthalenecarboxylic acids as 1-carba bioisosteres of oxolinic acid. J Med Chem 27:306–310PubMedCrossRefGoogle Scholar
  21. Koga H, Itoh A, Murayama S, Suzue S, Irikura T (1980) Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted l-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids. J Med Chem 23:1358–1363PubMedCrossRefGoogle Scholar
  22. Matsumoto J, Miyamoto T, Minamida A, Nishimura Y, Egawa H, Nishimura H (1984) Pyridonecarboxylic acids as antibacterial agents. 2 Synthesis and structure-activity relationships of 1,6,7-trisubstituted 1,4-dmydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, including enoxacin, a new antibacterial agent J Med Chem 27:292–301PubMedCrossRefGoogle Scholar
  23. Matsumoto J, Miyamoto T (1989) Cinoxacin analogues as potential antibacterial agents: synthesis and antibacterial activity In: Fernandes PB (ed) Quinolones, Prous Science Publishers, Barcelona, Spain p 115Google Scholar
  24. Mitscher LA, Gracey HE, Clark GW, Suzuki T (1978) Quinolone antimicrobial agents. 1. Versatile new synthesis of l-alkyl-l,4-dihydro-4-oxo-3-quinolinecarboxylic acids. J Med Chem 21:485–489PubMedCrossRefGoogle Scholar
  25. Mitscher LA, Sharma PN, Chu DTW, Shen LL, Pemet AG. Chiral DNA gyrase inhibitors. 1 Synthesis and antimicrobial activity of the enantiomers of 6-fluoro-7-(1-piperazinyl)-1-(2-trans-phenyl-1′-cyclopropyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. J Med Chem 29:2044–2047Google Scholar
  26. Mitscher LA, Sharma PN, Chu DTW, Shen LL, Pemet AG (1987) Chiral DNA gyrase inhibitors. 2 Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (Ofloxacin). J Med Chem 30:2283–2286PubMedCrossRefGoogle Scholar
  27. Narita H, Konishi Y, Nitta J, Nagaki H, Kobayashi Y, Watanabe Y, Minami S, Saikawa I (1986a) Pyridonecarboxylic acids as antibacterial agents. IV. Synthesis and structure-activity relationships of 7-amino-1-aryl-6-fluoro-4-quinolone-3-carboxylic acids. Yakugaku Zasshi 106:795–801PubMedGoogle Scholar
  28. Narita H, Konishi Y, Nitta J, Kitayama I, Watanabe Y, Miyazime M, Minami S, Yotsuji A, Saikawa I (1986b) Pyridone carboxylic acids as antibacterial agents. V. Synthesis and structure-activity relationship of 7-amino-6-fluoro-1-(fluorophenyl)-4-oxo-l,8-naphthyridine-3-carboxylic acids. Yakugaku Zasshi 106:802–807PubMedGoogle Scholar
  29. Nishimura Y, Matsumoto J (1987) Pyridonecarboxylic acids as antibacterial agents. 9 Synthesis and antibacterial activity of 1-substituted 6-fluoro-1,4-dihydro-4-oxo-7(4-pyridyl)-1,8-naphthyridine-3-carboxylic acids. J Med Chem 30:1622–1625PubMedCrossRefGoogle Scholar
  30. Nishimura Y, Minamida A, Matsumoto J (1988) Pyridonecarboxylic acids as antibacterial agents. XII. Synthesis and antibacterial activity of enoxacin analogs with a variant at position 1. Chem Pharm Bull (Japan) 36:1223–1228CrossRefGoogle Scholar
  31. Rosen T, Chu DTW, Lico IM, Fernandes PB, Shen L, Borodkin S, Pernet AG (1988a) Asymmetric synthesis and properties of the enantiomers of the antibacterial agent 7-(3-aminopyrrolidin-l-yl)-1-(2,4-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride. J Med Chem 31:1586–1589PubMedCrossRefGoogle Scholar
  32. Rosen T, Chu DTW, Lico IM, Fernandes PB, Marsh K, Shen L, Cepa VG, Pemet AG (1988b) Design, synthesis and properties of (4S)-7-(4-amino-2-substituted-pyrrolidin-l-yl)quinolone-3-carboxylic acids. J Med Chem 31:1598–1611PubMedCrossRefGoogle Scholar
  33. Sanchez JP, Domagala JM, Hagen SE, Heifetz CL, Hutt MP, Nichols JB, Trehan AK (1988) 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 31:983–991PubMedCrossRefGoogle Scholar
  34. Shen LL, Mitscher LA, Sharma PN, O’Donnell TJ, Chu DWT, Cooper CS, Rosen T, Pemet AG (1989) Mechanism of inhibition of DNA gyrase by quinolone antibactenals: A cooperative drug-DNA binding model. Biochemistry 28:3886–3894PubMedCrossRefGoogle Scholar
  35. Sutcliffe JA (1988) Novel approaches toward discovery of antibacterial agents. Annu Reports Med Chem 23:141–150CrossRefGoogle Scholar
  36. Uno T, Takamatsu M, Inoue Y, Kawahata Y, Iuchi K, Tsukamoto G (1987) Synthesis of antimicrobial agents. 1. Syntheses and antibacterial activities of 7-(azole substituted) quinolones. J Med Chem 30:2163–2168PubMedCrossRefGoogle Scholar
  37. Wentland MP, Bailey DM, Comett JB, Comett JB, Dobson RA, Powles RG, Wagner RB (1984) Novel amino-substituted 3-quinolinecarboxylic acid antibacterial agents: synthesis and structure-activity relationships. J Med Chem 27:1103–1108PubMedCrossRefGoogle Scholar
  38. Wentland MP, Pemi RB, Dorff PH, Rake JB (1988) Synthesis and bacterial DNA gyrase inhibitory properties of a spirocyclopropylquinolone derivative. J Med Chem 31:1694–1697PubMedCrossRefGoogle Scholar
  39. Yanagisawa H, Nakao H, Ando A (1973) Studies on chemotherapeutic agents. I Syntheses of quinoline and naphthyridine sulfonamide or phosphonic acid derivatives. Chem Pharm Bull (Tokyo) 21:1080–1089CrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Limited 1990

Authors and Affiliations

  • L. A. Mitscher
  • P. V. Devasthale
  • R. M. Zavod

There are no affiliations available

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