Advertisement

Azithromycin and novel azalides

  • Wolfgang Schönfeld
  • Stjepan Mutak
Chapter
Part of the Milestones in Drug Therapy MDT book series (MDT)

Abstract

Macrolides represent a well-known family of oral antibiotics. Their spectrum of activity covers most relevant bacterial species responsible for upper and lower respiratory tract infections. In 1952 the first macrolide, erythromycin, was introduced into the market. Erythromycin is active against gram-positive and certain gram-negative microorganisms and is still used to treat infections of the respiratory tract, skin and soft tissues, and genital tract. Macrolides express their antibiotic activity by inhibition of protein synthesis by binding to a 50S ribosome subunit. The precise mode of action is reported elsewhere in this monograph.

Keywords

Antibacterial Activity Antimicrob Agent Macrolide Antibiotic Ring Opening Reaction Macrolide Resistance 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1a.
    Kirst HA (1990) Structural modification of macrolide antibiotics Recent progress in the chemical synthesis of antibiotics. Springer-Verlag, Berlin-Heidelberg, 39–63Google Scholar
  2. 1b.
    Kirst HA (1996) Expanding the role of macrolide compounds as therapeutic agents, Progress in medicinal chemistry, Harwood Academic Publisher, Amsterdam, 1: 1–47Google Scholar
  3. 1c.
    Kirst HA (1998) Recent developments with macrolide antibiotics. Exp Opin Ther Patents 8: 111–120CrossRefGoogle Scholar
  4. 2a.
    Omura S (1984) Macrolide antibiotics. Chemistry,biology and practice. Academic Press Inc. Orlando, FLGoogle Scholar
  5. 2b.
    Neu HC, Young LS, Zinner SH, Acar JF (eds) (1995) New macrolides azalides and streptogramins in clinical practice. Marcel Dekker, New YorkGoogle Scholar
  6. 3.
    Bryskier AJ, Agouridas C, Chantot J-F (1993) New insights into the structure-activity relationship of macrolides and azalides. In: AJ Bryskier, J-P Butzler, HC Neu, PM Tulkens; (eds): Macrolides: Chemistry pharmacology and clinical uses. Arnette Blackwell, Paris, 3–30Google Scholar
  7. 4.
    Gasc JC, d’Ambrieres GS, Lutz A, Chantot JF (1991) New ether oxime of erythromycin A; a structure activity relationship study. J Antibiotics 44: 313–330CrossRefGoogle Scholar
  8. 5.
    Counter FT, Ensminger PW, Preston DA, Wu C-YE, Greene JM, Felty-Duckworth AM, Paschal JW, Kirst HA (1991) Synthesis and antimicrobial evaluation of dirithromycin, a new macrolide antibiotic. Antimicrob Agents Chemother 35: 1116–1126PubMedCrossRefGoogle Scholar
  9. 6.
    Watanabe Y, Morimoto S, Adachi T, Kashimura M, Asaka T (1993) Chemical modification of erythromycins IX. Selective methylation at the C-6 hydroxyl group of erythromycin A oxime derivatives and preparation of clarithromycin. J Antibiot 46: 647–660PubMedCrossRefGoogle Scholar
  10. 7.
    Ðokić S (1988) From erythromycin to azithromycin — From macrolides to azalides. Saopćenja 31: 3–39, Edition Pliva, ZagrebGoogle Scholar
  11. 8.
    Agouridas C, Denis A, Auger J-M, Beneddeti Y, Bonnefoy A, Bretin F, Chantot J-F, Dussarat A, Fromentin C, D’Ambrieres SG et al (1998) Synthesis and antibacterial activity of ketolides (6–0- methy1–3-oxoerythromycin derivatives): a new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens. J Med Chem 41: 4080PubMedCrossRefGoogle Scholar
  12. 9a.
    Ma Z, Clark RF, Wang S, Nilius AM, Flamm RK, Or Y (1999) Design, synthesis and characterization of ABT-773: A novel ketolide highly active against multidrug resistant pathogens. 39th ICAAC San Francisco, California, Abstr. F-2133 Google Scholar
  13. 9b.
    Or YS, Clark RF, Wang S, Chu DTW, Nilius AM, Flamm RK, Mitten M, Ewing P, Alder J, Ma Z (2000) Design, synthesis and antimicrobial activity of 6–0-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 43: 1045–1049PubMedCrossRefGoogle Scholar
  14. 10.
    Ðokić S, Tamburašev Z (1967) Erythromycin study: 9-amino-3–0-cladinosy1–6,11,12-trihydroxy2,4,6,8,10,12-hexamethylpentadecane-13-olide. Tetrahedron Lett 17: 1645–1647Google Scholar
  15. 11.
    Tamburašev Z, Vazdar G, Ðokić S (1967) Erythromycin series II: Acylation of erythromycin oxime and 9-amino-3–0-cladinosyl 5 0 desosaminy1–6,11,12-trihydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide with ester chlorides of dicarboxylic acids. Croat Chem Acta 3: 273–276Google Scholar
  16. 12.
    Kobrehel G, Tamburašev Z, Ðokić S (1977) Erythromycin series IV. Thin-layer of erythromycin, erythromycin oxime, erythromycylamine and their acyl derivatives. J Chromatography 133: 415–419CrossRefGoogle Scholar
  17. 13.
    Kobrehel G, Ðokić S (Pliva) (1981) Nouveaux derives de l’erythromycine A, procede pour leur preparation et leur utilisation comme substances antibacteriennes, Belg.P. 892 357, July 1, 1982, Prior.Yug. March 6,1981Google Scholar
  18. 14.
    Kobrehel G and Ðokić S (Pliva) (1981)11—Methy1–11-aza-4–0-cladinosy1–6–0-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyloxacyclopentadecane-2-one and derivatives thereof. USP 4 517 359, May 14, 1985, Prior.Yug March 6,1981Google Scholar
  19. 15.
    Kobrehel G, Radobolja G, Tamburašev Z and Ðokić S (Pliva) (1982), 11-Aza-10-deoxo-10- dihydroerythromycin A and derivatives thereof as well a process for their preparation. USP 4 328 334Google Scholar
  20. 16.
    Ðokić S, Kobrehel G, Lazarevski G, Lopotar N, Tamburašev Z, Kamenar B, Nagl A and Vickovi ć I (1986), Erythromycin series. Part 11. Ring expansion of erythromycin A oxime by the Beckmann rearrangement. J Chem Soc Perkin Trans I 1881–1990Google Scholar
  21. 17.
    Ðokić S, Kobrehel G, Lopotar N, Kamenar B, Nagl A, Mrvoš D (1988) Erythromycin series. Part 13. Synthesis and structure elucidation of 10-dihydro-10-deoxo-11-methyl-11-azaerythromycin A. J Chem Research (S) 1988: 152–153Google Scholar
  22. 18.
    Bright GM (Pfizer) (1984) Antibacterial N-methyl 11-aza-10-deoxo-10-dihydro-erythromycin A and pharmaceutically acceptable acid addition salts thereof, intermediates therefore, and processes for their preparation. USP 4 474 768, Oct. 2,1984, Prior. Nov. 15, 1982Google Scholar
  23. 19.
    Bright GM, Nagel AA, Bordner J, Desai KA, Dibrino JN, Nowakowska J, Vincent L, Watrous RM, Sciavolino FC, English AR et al (1988) Synthesis in vitro and in vivo activity of novel 9- deoxo-9a-aza-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides. J Antibiot 41: 1029–1047PubMedCrossRefGoogle Scholar
  24. 20.
    Allen DJM, Nepveux KM (Pfizer) (1989) Non-hygroscopic, azithromycin (9-deoxo-9a-aza-9amethyl-9a-homoerythromycin) dihydrate and a process therefor. PCT US87 01612, Jan. 26, 1989, Prior. US July 9, 1987Google Scholar
  25. 21.
    Kamenar B, Nagl A, Mrvoš D (1987) Structural investigations of 11-methylaza-10-deoxo-10- dihydroerythromycin A (DCH3). 10th Meeting of chemists of Croatia, Zagreb, Feb. 16–18, 1987, Abstr. No A-2, Abstr. book p. 29Google Scholar
  26. 22.
    Ðokić S,Kobrehel G, Lazarevski G (1987) Erythromycin series XII. Antibacterial in vitro evaluation of 10-dihydro-10-deoxo-11-azaerythromycin A: synthesis and structure activity relationship of its acyl derivatives. J Antibiot 40: 1006–1015CrossRefGoogle Scholar
  27. 23.
    Ðokić S, Vajtner Z, Lopotar N, Mrvoš -Sermek D, Kamenar D, Nagl A (1995) Complexes of azithromycin with some divalent metal ions. Croatica Chemica Acta 68: 375–381Google Scholar
  28. 24.
    Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, Borovoy R, Brenan L, Mason R (1987) Spectrum and mode of action of azythromycin (CP-62,993), a new 15membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrob Agent Chemother 31: 1939–1947CrossRefGoogle Scholar
  29. 25.
    Fiese EF, Steffen SH (1990) Comparism of the acid stability of azythromycin and erythromycin A. J Antimicrob Chemother 25: 39–47PubMedCrossRefGoogle Scholar
  30. 26.
    Girard AE, Girard D, English AR, Gotz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA (1987) Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half life and excellent tissue distribution. Antimicrob Agent Chemother 31: 1948–1954CrossRefGoogle Scholar
  31. 27.
    Foulds G, Shepard RM, Johnson RB (1990) The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 25: 73–82PubMedCrossRefGoogle Scholar
  32. 28.
    Schonwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M (1991) Comparism of three-day and five-day courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Microbiol Infect Dis 10: 877–880PubMedCrossRefGoogle Scholar
  33. 29.
    Drew R, Gallis H (1992) Azithromycin-spectrum of activity, pharmacokinetics and clinical applications. Pharmacotherapy 12: 161–173PubMedGoogle Scholar
  34. 30.
    Schentag J, Ballow C (1991) Tissue directed pharmacokinetics. Am J Med 91(suppl 3 A): 3–11Google Scholar
  35. 31.
    Lazarevski G, Vinković M, Kobrehel G, Ðkić S, Metelko B and Vikić-Topić D (1993) Conformational analysis of azithromycin by nuclear magnetic resonance spectroscopy and molecular modelling. Tetrahedron 49: 721–730CrossRefGoogle Scholar
  36. 32.
    Awann A, Brennan RJ, Regan AC, Barber J (1995) Conformational analysis of the erythromycin analogues azithromycin and clarithromycin in aqueous solution and bound to bacterial ribosomes. J Chem Soc, Chem Commun 1995: 1653–1654CrossRefGoogle Scholar
  37. 33.
    Yang BV, Goldsmith M, Rizzi (1994) A novel product from Beckmann rearrangement of erythromycin A 9(E) oxime. Tetrahedron Lett 55: 3025–3028CrossRefGoogle Scholar
  38. 34.
    Fattori R, Pelacini F, Romagnano S, Fronza G, Rallo R (1996) Unusual isoxaline formation by intramolecular cyclization of (9E)-erythromycin oxime. J Antibiot 49: 938–940CrossRefGoogle Scholar
  39. 35.
    Wilkening RR, Ratcliffe RW, Doss GA, Mosley RT, Ball RG (1997) Novel transanular rearrangements of azalide iminoethers. Tetrahedron 53: 16923–16944.CrossRefGoogle Scholar
  40. 36a.
    Wilkening RR, Ratcliffe RW, Doss GA, Bartizal KF, Graham AC, Herbert CM (1993) The synthesis of novel- 8a-aza-8a-homoerythromycin derivatives via the Beckmann rearrangement of (9Z)-erythromycin A oxime. Bioorg Med Chem Lett 3: 1287–1292CrossRefGoogle Scholar
  41. 36b.
    Wilkening RR (Merck) (1993) 8a-Aza-8a-homoerythromycin lactams. USP 5,202,434, Apr. 13,1993, Prior. US Mar. 27, 1992.Google Scholar
  42. 37.
    Lazarevski G, Vinković M, Kobrehel G, Ðokić S, Metelko B (1994) Conformational analysis of 9-deoxo-9a-aza-9a-and 9-deoxo-8a-aza-8a-homoerythromycin A 6,9-cyclic iminoethers. Tetrahedron 50: 12201–12210CrossRefGoogle Scholar
  43. 38.
    Kamenar B, Mrvol-Sermek D, Nagl A (1996) Crystal structure of 9-deoxo-9-dihydro-9a-(npropyl)-9a-aza-9a-homo-erythronolide A, C24H47NO7. Zeitschrift für Kristallographie 211: 415–417CrossRefGoogle Scholar
  44. 39.
    KujundŽić N, Kobrehel G, Banie Z, Kelnerić Ž, Kojić-Prodić B (1995) Azalides: Synthesis and antibacterial activity of novel 9a-N-(N’-substituted carbamoyl and thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A. Eur J Med Chem 30: 455–462CrossRefGoogle Scholar
  45. 40.
    Sheldrick GM, Kojic-Prodic B,Banic Z,Kobrehel G,KujundžićN(1995) Structure of 9-Deoxo9a-N-(N’-(4’-pyridyfi-carbamoy1)-9a-Aza-9a-homoerythromycin A and conformational analysis of analogous 9a-aza 15-membered azalides in solid state. Acta Cryst B51: 358–366Google Scholar
  46. 41.
    Asaka TT, Misawa YT, Kashimura MT, Morimoto ST, Hatayama KT (Taisho) (1994) 5–0- Desosaminylerythronolide derivative. EP 0 619 320, 12 Oct. 1994, Prior. JP 27 Dec. 1991Google Scholar
  47. 42.
    Kobrehel G, Lazarevski G, Ðokić S, KolaCni-Babie L, Kucišec-TepešN, Cvrlje M (1992) Synthesis and antibacterial activity of O-methylazithromycin derivatives. J Antibiot 45: 527–534PubMedCrossRefGoogle Scholar
  48. 43.
    Waddell ST, Santorelli GM, Blizzard TA, Graham A, Occi J (1998) Synthesis and antibacterial activity of 0-methyl derivatives of azalide antibiotics: I. 4“, 11 and 12–0-Me derivatives via direct methylation. Bioorg Med Chem Lett 8: 549–554PubMedCrossRefGoogle Scholar
  49. 44.
    Kamenar B, Košutić-Hulita N, Vickovie I, Kobrehel G, Lazarevski G (1996) 11,12,4“-Tri-Omethylazythromycin monohydrate. Acta Cryst C52: 2566–2568Google Scholar
  50. 45.
    Waddell ST, Santorelli GM, Blizzard TA, Graham A and Occi J (1998) Synthesis and antibacterial activity of 0-methyl derivatives of azalide antibiotics: II: 6–0-Me derivatives via clarithromycin. Bioorg Med Chem Lett 8: 1321–1326PubMedCrossRefGoogle Scholar
  51. 46.
    Denis A, Agouridas C (1998) Synthesis of 6–0-methyl-azithromycin and its ketolide analogue via Beckmann rearrangement of 9(E)-6–0-methyl-erythromycin oxime. Bioorg Med Chem Lett 8: 2427–2432PubMedCrossRefGoogle Scholar
  52. 47.
    Kobrehel G, Lazarevski G, Kelnerić Ž, Ðokić S (1993) 9a, 11-Cyclic carbamates of 15-membered azalides. J Antibiot 46: 1239–1245PubMedCrossRefGoogle Scholar
  53. 48.
    Wu YJ, Wons R, Durkin D, Goldsmith M, Su WG, Rainville J, Smyth K, Yang BV, Massa M, Kane J, et al (1998) Synthesis and in vitro activity of novel C-4 carbamates of 14- and 15-membered macrolides. 38th ICAAC, San Diego, California, Abstract F-123Google Scholar
  54. 49.
    Cheng H, Letavic MA, Ziegler CB, Dutra JK, Bertinato P, Bronk BS (Pfizer) (2000) C11 Carbamates of macrolide antibacterials. EP 0 984 019 Al, Mar. 8, 2000, Prior. US Aug. 19, 1988Google Scholar
  55. 50.
    Waddell ST, Blizard TA (1993) Chimeric azalides with simplified western portions. Tetrahedron Lett 34: 5385–5388CrossRefGoogle Scholar
  56. 51.
    Waddell ST, Blizard TA (1992) Base catalysed ring opening reactions of erythromycin A. Tetrahedron Lett 33: 7827–7830CrossRefGoogle Scholar
  57. 52.
    Waddell ST, Blizard TA (1993) Semisynthesis of linear fragments corresponding to the eastern portion of azalide antibiotics. Bioorg Med Chem Lett 3: 1757–1760CrossRefGoogle Scholar
  58. 53.
    Lazarevski G, Kobrehel G, Naranda A, Banić-Tomišić Z, Metelko B (1998) Acid catalised ring opening reactions of 6-deoxy-9-deoxo-9a-aza-9a-homoerythromycin 6,9-cyclic imino ether. J Antibiot 51(9): 893–896PubMedCrossRefGoogle Scholar
  59. 54.
    Lazarevski G, Kobrehel G, Metelko B, Duddeck H (1996) Ring opening reactions of 6-deoxy-9- deoxo-9a-aza-9a-homoerythromycin 6,9-cyclic imino ether. J Antibiot 49(10): 1066–1069PubMedCrossRefGoogle Scholar
  60. 55.
    Rafka RJ, Morton BJ, Ragan CB, Bertinato P, Dirlam JP, Blize AE, Ziegler CB (Pfizer) (2000) 13-Membered azalides and their use as antibiotic agents.PCT WO 00/31097, 2 June 2000, Prior. US 20 Nov. 1998.Google Scholar
  61. 56.
    Leclercq R, Courvalin P (1991) Bacterial resistance to macrolide, lincosamide and streptogramin antibiotics in bacteria. Antimicrob Agents Chemother 35: 1267–1272PubMedCrossRefGoogle Scholar
  62. 57.
    Weisblum B (1995) Erythromycin resistance by ribosome modification. Antimicrob Agents Chemother 39: 577–585PubMedCrossRefGoogle Scholar
  63. 58.
    Corbaz L, Ettlinger L, Gauman E, Keller W, Kradolfer F, Kyburz E, Neipp L, Prelog V, Reusser R, Zahner H (1955) Stoffwechselprodukte von Actinomyceten. Narbomycin. Hely Chim Acta 35: 935–942CrossRefGoogle Scholar
  64. 59.
    Brockmann H, Henkel W (1951) Picromycin, eM bitter schmeckendes Antibioticum aus Actinomyceten. Chem Ber 84: 284–288CrossRefGoogle Scholar
  65. 60.
    Allen N (1977) Macrolide resistance in Staphylococcus aureus: inducers of macrolide resistance. Antimicrob Agents Chemother 11: 669–674Google Scholar
  66. 61.
    Kobrehel G, Lazarevski G, Vinković M (Pliva) (1999) Novel 3,6-hemiketals from the class of 9aazalides. Pat. WO-09920693, 29 Apr. 1999, Prior.HR 10 Sep. 1998Google Scholar
  67. 62.
    Denis A, Agouridas C, Auer J-M, Beneddeti Y, Bonnefoy A, Bretin F, Chantot J-F, Dussarat A, Fromentin C, D’Ambrieres SG et al (1999) Synthesis and antibacterial activity of HMR 3647, a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 9: 3075–3080PubMedCrossRefGoogle Scholar
  68. 63.
    Blizzard TA, Waddell ST, Santorelli GM (Merck) (1999) 9a-Aza-3-ketolides, compositions containing such compounds and methods of treatment. PCT 99/00125, 7 Jan. 1999, Prior US 27 June 1997Google Scholar
  69. 64.
    Blizzard TA, Santorelli GM (Merck) (1999) 8a-Azalides, compositions containing such compounds and methods of treatment. PCT 99/19331, 22 Apr. 1999, Prior US 16 Oct. 1997Google Scholar
  70. 65.
    Lazarevski G, Kobrehel G and Kelnerić Ž (Pliva) (1999) 15-Membered lactams ketolides with antibacterial activity. Patent WO-09951616, 14 Oct. 1999, Prior. HR 06 Apr. 1998Google Scholar
  71. 66.
    Debono M, Willard KE, Kirst HA, Wind JA, Crouse GO, Tao EV, Vicenzi JT, Counter FT, Ott JL, Ose EE, et al (1989) Synthesis and antimicrobial evaluation of 20-deoxo20-(3,5-dimethylpiperidin-1-y1)-desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives. J Antibiot 42: 1253–1267PubMedCrossRefGoogle Scholar
  72. 67.
    Naranda A, Šušković B, Kelnerić Ž,Ðokić S (1994) Structure-activity relationship among polyhydro derivatives of tylosin. J Antibiot 47: 581–587CrossRefGoogle Scholar
  73. 68.
    Naranda A, Kelnerić Ž, Kolacni-Babić L, Ðokić S (1995) 10,11,12,13-Tetrahydro derivatives of tylosin. Synthesis, antibacterial activity and tissue distribution of 4’-deoxy-10,11,12,13-tetrahydrodesmycosin. J Antibiot 48: 284–253Google Scholar
  74. 69.
    Lopotar N, Ðokić S (Pliva) (1990) Preparation and properties of some tylosine derivatives. EP 041043381, Prior. YU July 26, 1989Google Scholar
  75. 70.
    Naranda A, Lopotar N, Kelnerić Ž (1998) Synthesis of novel dihydro and tetrahydro desmycosin derivatives. ICMASK 4, Fifth International Conference on the Macrolides, Azalides, Streptogramins and Ketolides Barcelona, Spain, Abstr. 1.29Google Scholar
  76. 71.
    Lopotar N, Naranda A, Vela V, Ðerek M, Maškć N (2000) Synthesis and microbiological activity of 17-membered azalides. ICMAS-KO 5, Fifth International Conference on the Macrolides, Azalides, Streptogramins, Ketolides and Oxazolidinones Seville, Spain, Abstr. 1.01Google Scholar
  77. 72.
    Grdiša M, Lopotar N, Pavelić K (1998) Effect of a 17-member azalide on tumor cell growth. Chemotherapy 44: 331PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  • Wolfgang Schönfeld
    • 1
  • Stjepan Mutak
    • 1
  1. 1.PLIVA ResearchAntiinfective ResearchZagrebCroatia

Personalised recommendations