Aptula, A.O.; Netzeva, T.I.; Valkova, I.V.; Cronin, M.T.D.; Schultz, T.W.; Kühne, R.; Schüürmann, G. Multivariate Discrimination between Modes of Toxic Action of Phenols. Quant. Struct.-Act. Relat. 2002, 21, 1, 12–22.

Abstract

A set of 221 phenols, for which toxicity data to the ciliate Tetrahymena pyriformis were available, was subjected to stepwise linear discriminant analysis (LDA) in order to classify their toxic mechanisms of action. The compounds were a priori grouped into the following four mechanisms according to structural rules: polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Hydrophobicity with and without correction for ionisation (log Kow, log Dowu), acidity constant (pKa), frontier orbital energies (ELUMO, EHOMO) and hydrogen-bond donor and acceptor counts were used as molecular descriptors. LDA models employing 3–6 variables achieved 86–89% overall correct classification of the four mechanisms, with more varied performance for respiratory uncouplers and pro-electrophiles. For the latter, a separate model was developed that discriminated compounds undergoing metabolic activation from compounds with different mechanisms very accurately. Model validation was performed by evaluating the simulated external prediction through LDA models built from complementary subsets.