Mechanism-based quantitative structure-activity relationships for the inhibition of substituted phenols on germination rate of Cucumis sativus

摘要

Comparative inhibition activity (GC_(50)) of 42 structurally diverse substituted phenols on seed germination rate of Cucumis sativus was investigated. Quantitative structure-activity relationships (QSARs) were developed by using hy-drophobicity (1-octanol/water partition coefficient, log K_(ow)) and electrophilicity (the energy of the lowest unoccupied molecule orbital, E_(lumo)) for the toxicity of phenols according to their modes of toxic action. Most phenols elicited their response via a polar narcotic mechanism and a highly significant log K_(ow)-based model was obtained (GC_(50) = 0.92 log K_(ow) + 1.99, r~2 = 0.84, n = 29). The inclusion of E_(lumo) greatly improved the predictive power of the polar narcotic QSAR (GC_(50)= 0.88 log K_(ow) - 0.30E_(lumo) + 1.99, r~2 = 0.93, n = 29). pK_a proved to be an insignificant influencing factor in this study. Poor correlation with hydrophobicity and strong correlation with electrophilicity were observed for the nine bio-reactive chemicals. Their elevated toxicity was considerably underestimated by the polar narcotic log K_(ow)-dependent QSAR. The nine chemicals consist of selected nitro-substituted phenols, hydroquinone, catechol and 2-aminophenol. Their excess toxic potency could be explained by their molecular structure involving in vivo reaction with bio-macromolecules. Strong dissociation of carboxyl group of the four benzoic acid derivatives greatly decreased their observed toxicity. In an effort to model all chemicals including polar narcotics and bio-reactive chemicals, a response-surface analysis with the toxicity, logK_(ow) and E_(lumo) was performed. This resulted in a highly predictive two-parameter QSAR for most of the chemicals (GC_(50) = 0.70 logK_(ow) - 0.66E_(lumo) + 2.17, r~2 = 0.89, n = 36). Catechol and 2,4-dinitrophenol proved to be outliers of this model and their much high toxicity was explained.