Abstract
A diverse series of amides were evaluated for aquatic toxicity (IGC50) assessed in the Tetrahymena pyriformis population growth impairment assay and for reactivity (EC50) with the model soft nucleophile thiol in the form of the cysteine residue of the tripeptide glutathione. All alkylamides along with some halo-substituted amides are well predicted by the simple hydrophobicity (log K ow)–electrophilicity (E lumo) response-surface model [log(IGC−1 50) = 0.45(log K ow) − 0.342(E lumo) − 1.11]. However, 2-halo amides with the halogen at the end of the molecule and α,β-unsaturated primary amides are among those derivatives identified as being more toxic than predicted by the model. Amides, which exhibit excess toxicity, were capable of forming covalent bonds through an SN2 displacement or a Michael addition. Moreover, only those amides exhibiting excess toxicity were reactive with thiol, suggesting that the reactivity with model nucleophiles such as the thiol group may provide a means of accurately defining reactive toxicants.
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Abbreviations
- DMSO:
-
dimethyl sulfoxide
- DTNB:
-
5,5′-dithiobis(2-nitrobenzoic acid)
- E lumo :
-
energy of the lowest unoccupied molecular orbital
- GSH:
-
glutathione
- IGC50 :
-
50% growth inhibitory concentrations
- log K ow :
-
1-octanol–water partition coefficients
- QSAR:
-
quantitative structure–activity relationship
- REACH:
-
Registration, Evaluation, and Authorization of Chemicals
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Schultz, T.W., Yarbrough, J.W. & Koss, S.K. Identification of reactive toxicants: Structure–activity relationships for amides. Cell Biol Toxicol 22, 339–349 (2006). https://doi.org/10.1007/s10565-006-0079-z
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DOI: https://doi.org/10.1007/s10565-006-0079-z