QSAR of Acute Toxicity of 1,4-Di-Substituted Benzene Derivatives and Relationships with the Acute Toxicity of Corresponding Mono-Substituted Benzene Derivatives

Abstract

Over one hundred di-substituted benzene derivatives of the general formula 1-R-C6H4-X, where R = CI, OH, NH2, N02, and N(CH3)2, and where X is an aliphatic or aromatic group, including but not limited to X = CONH2, CI, CH2OH, CH3, OCH3, Br, CF3, CN, NO2, C6H5, OC6H5, and N=N=C6H5, were tested for acute toxicity to Photobacterium phosphoreum in the Microtox™ test. For the entire set of compounds, the observed toxicity range is close to five orders of magnitude on a molar basis. Quantitative structure-toxicity computations (QSAR) of the complete data set and the five subsets (as defined by R) show varying degrees of correlation with the octanol/water partition coefficients (log P) with the subset for R = N02 having the lowest (r2 = 0.02; n = 35) and that for r = CI having the highest (r2 = 0.35; n = 41) correlation with log P. It is also found that the observed toxicities are more highly correlated with the acute toxicities of the corresponding mono-substituted benzene derivatives of the same general formula with R = H, both for the entire set (r2 = 0.33; n = 133) and each of the subsets, particularly so for R = CI (r2 = 0.71; n = 35). After elimination of highly toxic compounds, the remaining set of 105 di-substituted benzene derivatives is significantly gorrelated with their log P and the toxicities of mono-substituted benzenes (r2 = 0.71; s = 0.34; n = 105). The results indicate a significant improvement in reliability of toxicity prediction by using the toxicity values of structurally-related compounds together with log P.