QSAR models for both mutagenic potency and activity: Application to nitroarenes and aromatic amines

Abstract

We studied the molecular determinants that discriminate between mutagenic and inactive compounds for: a) aromatic and heteroaromatic amines; b) nitroarenes. Mutagenic activity (data from literature) had been previously assessed in Salmonella typhimurium and Escherichia coli (SOS repair). The Quantitative Structure-Activity Relationships (QSAR) found were compared with those obtained in the laboratory of Professor C. Hansch for the mutagenic potency of the same compounds. It appears that there is a dramatic difference between the QSARs for potency, and those for yes/no activity: hydrophobicity played a major role in determining the potency of the active compounds, whereas mainly electronic factors differentiated the actives from the inactives. The electronic factors were those expected on the basis of the hypothesized metabolic pathways of the chemicals. Our interpretation is that the electronic factors (together with size/shape, possibly) determine the minimum requirement for the chemicals to be metabolized, whereas the hydrophobicity determines the extent of activity of chemicals that can be metabolized (actives). Moreover, the different QSARs found for the Salmonella strains TA98 and TA100 were discussed in the light of recent progress in the understanding of the molecular mechanisms of mutagenicity in these organisms. It is concluded that the nonlinear relationship observed for these chemicals between the two types of QSAR should be taken into account both when planning QSAR studies, and when using mutagenicity data for risk assessment.