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

Abstract

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 72.5 to 1910 μmol/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 σ 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.