Structure-Teratogenicity Relationships Among Antifungal Triazoles

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.