Epoxide and Thiirane Toxicity In vitro with the Ciliates Tetrahymena pyriformis: Structural Alerts Indicating Excess Toxicity

摘要

The 48 h toxicity of 18 organic narcotics, 13 epoxides, and 2 thiiranes toward the ciliates Tetrahymena pyriformis was determined in terms of 50% growth inhibition ECS0. Nominal ECS0 was corrected for volatilization and sorption to quantify the freely dissolved compound fraction in solution. The derived baseline narcosis model served to evaluate toxicity enhancements Te as ratios of narcosis-predicted over experimental EC50 values. Among the nine heterocydes with aliphatic side chains that include two thiiranes, three compounds yielded Te > 10, suggesting their covalent binding at nudeophilic protein sites such as -OH, -NHR, and - SH through S^-type ring-opening. As a general trend of this group, Te decreases with increasing alkyl group size. Moreover, four of the six nonaliphatic epoxides exerted substantial excess toxicities with Te > 10, which could be rationalized by ring-opening activation through negative inductive effect, benzylic stabilization, and phenyl ring H-bonding. By contrast, 1,2 substituted epoxides showed narcosis-level toxicity, despite the opportunity of side-chain Schiff-base formation with protein amino groups. The resulting structural alerts enable an in silico screening of epoxides and thiiranes for their potential to exert excess toxicity. Note that observed differences in Te sensitivity between ciliates, bacteria and fish should be taken into account when designing in vitro alternatives to fish toxicity studies.