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Structure-Teratogenicity Relationships Among Antifungal Triazoles

  • Oliver P. Flint
  • F. Thomas Boyle
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 96)

Abstract

Following the observation that the antifungal agent ketoeonazole was teratogenic in rats (Symoens and Cauwenbergh 1983), we identified the triazole antifungal ICI 153,066 also as a teratogen in the rat (Flint and Boyle 1985). In an effort to elucidate structure-activity relationships, we tested 16 further monotriazoles for in vitro antifungal activity and for toxicity using a simple short-term in vitro test, the micromass teratogen test (Flint and Orton 1984; Flint 1987). The processes of mammalian embryogenesis and cell differentiation are retained in vitro so that an inhibition of cell differentiation is an indication that there may be a potential risk of teratogenicity in vivo (Flint 1987). Four monotriazoles with widely differing activity in the micromass test were investigated in the rat and good correlation found between in vivo teratogenicity and in vitro inhibition of cell differentiation (Flint and Boyle 1985). A correlation was also found between the water- octanol partition coefficient (log P) of the 16 monotriazoles and their in vitro anti-Candida and anti-differentiation activities. We have now extended this work to 35 monotriazole and 35 bistriazole compounds in a study which high-lights differences between the two structural types and considers the role of substituents in determining teratogenic hazard.

Keywords

Antifungal Activity Aromatic Nucleus Tertiary Alcohol Maternal Weight Gain Embryo Toxicity 
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. Boyle FT, Ryley JF, Wilson RG (1987) In vitro-in vivo correlations with azole antifungals. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous, Barcelona, ppSl:31-Sl:41Google Scholar
  2. Brown LP, Flint OP, Orton TC, Gibson GG (1986) In vitro metabolism of teratogens by differentiating rat embryo cells. Food Chem Toxicol 24: 737–742PubMedCrossRefGoogle Scholar
  3. Flint OP (1987) An in vitro test for teratogens using cultures of rat embryo cells. In: Atterwill CK, Steele GE (eds) In vitro methods in toxicology. Cambridge University Press, Cambridge, pp 339–363CrossRefGoogle Scholar
  4. Flint OP, Boyle FT (1985) An in vitro test for teratogens: its application in the selection of non-teratogenic triazole antifungals. Concepts in Toxicology 3: 29–35Google Scholar
  5. Flint OP, Brown LP (1987) Metabolism of teratogens by mammalian embryos: an in vitro investigation. In: Nau H, Scott WJ (eds) Pharmacokinetics in teratogenesis, vol II. CRC Press, Boca Raton, pp 133–144Google Scholar
  6. Flint OP, Orton TC (1984) An in vitro assay for teratogens with cultures of rat embryo midbrain and limb bud cells. Toxicol Appl Pharmacol 76: 383–395PubMedCrossRefGoogle Scholar
  7. Fujita T, Iwasa J, Hansch C (1964) A new substituent constant, n, derived from partition coefftcents. J Am Chem Soc 86: 5175–5180CrossRefGoogle Scholar
  8. Girling L, Flint OP (1984) Inhibition of embryonic-cell differentiation by teratogens in vitro: quantification using ELISA (enzyme linked immunosorbent assay). Hum Toxicol 3: 155–156Google Scholar
  9. Hansch C (1969) A quantitative approach to biochemical structure-activity relationships. Acc Chem Res 2: 232–239CrossRefGoogle Scholar
  10. Hansch C (1985) The QSAR paradigim in the design of less toxic molecules. Drug Metab Rev 15: 1279–1294CrossRefGoogle Scholar
  11. Hansch C (1989) Comparative structure-activity relationships. In: Fauchere JL (ed) Progress in clinical and biological research, vol 291, QSAR: quantitative structure-activity relationships in drug design. Liss, New York, pp 23–30Google Scholar
  12. Hansch, C Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley-Interscience, New YorkGoogle Scholar
  13. Hillebrand M, Sahini VE, Volanschi E (1977) Electronic structure of the chloro- benzenes in connection with their biological activity. Buletinul Institutului Politehnic Gheorghe Gheorghiu-Dej Bucuresti 39: 27–32Google Scholar
  14. Katiyar M, Gupta SP (1982) Synthesis and fungitoxicity of some l,3-di-(substituted phenyl) thioureas. Philippine J Sci 3: 65–70Google Scholar
  15. Khera KS (1984) Maternal toxicity - a possible factor in fetal malformations in mice. Teratology 29: 411–416PubMedCrossRefGoogle Scholar
  16. Lewis SJ, Mirlees MS, Taylor PJ (1983a) Rationalizations among heterocyclic partition coefficients. Part 1: The Jt-value of phenyl. Quant Struct Act Relationships 2: 1–6Google Scholar
  17. Lewis SJ, Mirlees MS, Taylor PJ (1983b) Rationalizations among heterocyclic partition coefficients Part 2: The azines. Quant Struct Act Relationships 2: 100–111Google Scholar
  18. Mirlees MS, Moulton SJ, Murphy CT, Taylor PJ (1976) Direct measurement of octanol-water partition coefficients by high-pressure liquid chromatography. J Med Chem 19: 615–619CrossRefGoogle Scholar
  19. Nelson SD (1982) Metabolic activation and drug toxicity. J Med Chem 25: 753–765PubMedCrossRefGoogle Scholar
  20. Richter JE, Peterson SF, Kleiner C (1983) Acute and chronic toxicity of some chlorinated benzenes, chlorinated ethanes and tetrachlorethylene to Daphnia magna. Arch Environ Contam Toxicol 12: 679–684PubMedCrossRefGoogle Scholar
  21. Schultz TW, Riggin GW (1985) Predictive correlations for the toxicity of alkyl- and halogen-substituted phenols. Toxicol Lett 25: 47–54PubMedCrossRefGoogle Scholar
  22. Symoens J, Cauwenbergh G (1983) Ketoconazole, a new step in the management of fungal disease. Prog Drug Res 27: 63–84PubMedGoogle Scholar
  23. Tachibana M, Noguchi Y, Monro AM (1987) Toxicology of fluconazole in experimental animals. In: Fromtling RA (ed) Recent trends in the discovery, development and evaluation of antifungal agents. JR Prous, Barcelona, pp 93–102Google Scholar
  24. Tanii H, Tsuji H, Hashimoto K (1986) Structure-toxicity relationship of monoketones. Toxicol Lett 30: 13–17PubMedCrossRefGoogle Scholar
  25. Toranzo EG, Gillessi T, Mendenhall M, Traiger GJ, Riley PG, Hanzlik RP, Wiley RA (1977) Effect of substituents on arene oxide-mediated liver toxicity among substituted bromobenzenes. Toxicol Appl Pharmacol 40: 415–425PubMedCrossRefGoogle Scholar
  26. Vanden Bossche H, Willemsens G, Cools W, Marichal P, Lauwers WF (1983) Hypothesis on the molecular basis of the antifungal activity of N-substituted imidazoles and triazoles. Biochem Soc Trans 11: 665–667PubMedGoogle Scholar
  27. Veith GD, De Foe D, Knuth M (1985) Structure-activity relationships for screening organic chemicals for potential ecotoxicity effects. Drug Metab Rev 15: 1295–1303CrossRefGoogle Scholar
  28. Wiley RA, Hanzlik RP, Gillesse T (1979) Effects of substituents on in vitro metabolism and covalent binding of substituted bromobenzenes. Toxicol Appl Pharmacol 49: 249–255PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Oliver P. Flint
  • F. Thomas Boyle

There are no affiliations available

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