Substituted aniline interaction with submitochondrial particles and quantitative structure-activity relationships

The toxic effects of eighteen substituted anilines were determined by means of a short-term in vitro assay, using submitochondrial particles (SMP) as biosensors; The assay allows for the quantification of the effects of toxicants that act specifically on mitochondrial respiratory functions, like uncouplers and inhibitors, or non-specifically, by disturbing the structure and functioning of the inner mitochondrial membrane. The obtained EC50 values range from 7.2.5 to 1910 mumol/l. The type and position of the substituents are of fundamental importance in determining the toxic potency. In general, the presence of electron-withdrawing substituents produces higher toxic effects, whereas electron-donating groups seem to reduce the toxicity. Quantitative structure-activity relationships (QSAR) showed that toxicity values were correlated with the Hammett sigma constant and with hydrogen bonding capacity descriptors, such as E-LUMO, E-HOMO and Q(+). The results indicate that toxicity increases with increasing the hydrogen bonding donor capacity of the NH2 group and support the hypothesis of a mechanism of action based on hydrogen bonding formation between the amino group of anilines and polar groups at the membrane/water interface. Such an interaction would cause a derangement of the membrane structure and, as a consequence, a disturbance of its functioning. (C) 2002 Elsevier Science B.V. All rights reserved.