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  • Quantum - chemical descriptors for estimating the acute toxicity of electrophiles to the fathead minnow (Pimephales promelas): An analysis based on molecular mechanisms


Estimating the toxicity of reactive xenobiotics to aquatic organisms requires pysicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Electrophiles whose toxic action is attributed to nucleophilic substitution (S(N)), Michael type addition and Schiff base formation were examined. Training sets were generated through substructure search applied to chemicals in a fathead minnow (Pimephales promelas) database. Relationships between modes of toxic action, potency (96 hour LC(50)) values) and mechanistically appropriate quantum chemical descriptors were explored. Monohalo-C(sp(3)) function which may give rise to S(N) reactivity was encountered in 35 compounds. The inclusion of E(LUMO) hydrophobicity relation increased the explained variance from R(2) between 36% to 69%. 18 potential Michael type acceptors were identified by the presence of a localized CC double bond at an alpha, beta position to a polar group. Two additional electronic descriptors that are consistent with the likely molecular mechanism provide a multivariate QSAR with R(2) at 0.78 45 aldehydes and 3 formamides comprised the training set associated with probable Schiff base mechanism of toxicity. It was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the compounds all contain a common electrophilic moiety related to the putative specific reaction mechanism.

Additional information

Authors: KARABUNARLIEV S, JRC Ispra (IT);KARCHER W, JRC Ispra (IT);MEKENYAN O G, Bourgas University of Technology, Department ofPhysics (BG);RUSSOM C L, US EPA, Duluth (US);BRADBURY S P, US EPA, Duluth (US)
Bibliographic Reference: Article: Quantitative Structures - Activity Relationships
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