Structure-Teratogenicity Relationships Among Antifungal Triazoles
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.
KeywordsAntifungal Activity Aromatic Nucleus Tertiary Alcohol Maternal Weight Gain Embryo Toxicity
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- Hansch, C Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley-Interscience, New YorkGoogle Scholar
- 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
- Katiyar M, Gupta SP (1982) Synthesis and fungitoxicity of some l,3-di-(substituted phenyl) thioureas. Philippine J Sci 3: 65–70Google Scholar
- 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
- Lewis SJ, Mirlees MS, Taylor PJ (1983b) Rationalizations among heterocyclic partition coefficients Part 2: The azines. Quant Struct Act Relationships 2: 100–111Google Scholar
- 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