Structure-toxicity analyses of Tetrahymena pyriformis exposed to pyridines- An examination into extension of surface-response domains

A selection of mechanistically diverse substituted pyridines were tested in the Tetrahymena pyriformis population growth impairment assay. The respons e-surface approach was used to derive multiple-regression type structure-to xicity relationships between T. pyriformis population growth impairment tox icity data (log(IGC(50)(-1))) and the 1-octanol/water partition coefficient (log K-ow) and one of two different descriptors of molecular orbital inter action: energy of the lowest unoccupied molecular orbital (E-LUMO) and maxi mum acceptor superdelocalizability (S-MAX). A statistically robust model (l og(IGC(50)(-1)) = -3.91 + 0.50(log K-ow)+ 10.70(S-MAX); n = 83, r(2) = 0.75 6, s = 0.38, F= 124, Pr > F = 0.0001) was developed with S-MAX as the indic ator of reactivity. This model was not statistically different in fit from the model (log(IGC(50)(-1)) = -1.19 + 0.56(log K-ow) - 0.61(E-LUMO); n = 86 , r(2) = 0.749, s = 0.38, F = 124, Pr > F = 0.0001) derived using the alter native descriptor of electrophilic interaction. Compounds with high residua l values were removed. An examination of these outliers from both response- surfaces, revealed that pyridines substituted in the 2-position with electr on-releasing groups and halogenated nitro-substituted pyridines did not fit the above models well. A third group of outliers, the mono-halogenated pyr idines, was unique to the S-MAX response-surface, which are neutral narcoti cs with potentially high volatility. A comparison of observed and predicted toxicities for a validation set of pyridines for the S-MAX surface (log(ob served IGC(50)(-1)) = 0.10 + 0.75(log (predicted IGC(50)(-1))); n = 10, r(2 ) = 0.662, s = 0.49, F = 15.7, Pr > F = 0.004) and the E-LUMO surface (log( observed IGC(50)(-1)) = 0.17 + 0.80(log (predicted IGC(50)(-1))); n = 10, r (2) = 0.707, s = 0.45, F= 19.3, Pr > F= 0.002) validated the above models, with the fit in the same range as the parent model. The model derived with S-MAX was compared to the response-surface derived for r(2) = 0.816, S = 0. 34, F = 429, Pr > F = 0.0001) revealing the similarities in slope and inter cept between the two response-surfaces. The model fit was poorer for the py ridine surface, which may be a factor of increased reactivity due to the pr esence of nitrogen and the associated pair of unshared electrons in the rin g not present in benzene. However. the similarity of the pyridine and benze ne response-surfaces suggests that the domain defined for benzenes may be e xtended to encompass nitrogen heterocyclic pyridines.