MUTAGENICITY OF NITRO-SUBSTITUTED AND AMINO-SUBSTITUTED CARBAZOLES IN SALMONELLA-TYPHIMURIUM .2. ORTHO-AMINONITRO DERIVATIVES OF 9H-CARBAZOLE

The mutagenicity of 4 ortho-aminonitrocarbazoles and 2 ortho-acetamidonitrocarbazoles was assayed in Salmonella strains TA1538, TA98, TA100, TA1537 and TA1977 and in nitroreductase and acetylase deficient strains TA98NR and TA98/1,8DNP(6), with and without S9 from phenobarbital-induced rat liver. Mutagenicity of these compounds and of their monosubstituted precursors (Andre et al., Mutation Res. 299 (1993) 63-73) was tentatively correlated with various molecular descriptors. The hydrophobicity appears as an important determinant of direct mutagenicity in this series of closely related nitrocarbazoles, with a general trend of increasing mutagenicity with an increase of hydrophobicity. On the contrary; the ease of nitroreduction (depicted by electrochemical reduction potential and energy of the lowest unoccupied molecular orbitals) does not appear as a major direct determinant. The ortho-amino group does not favour mutagenic potential, except for 1-nitro-2-aminocarbazole, which is the most potent direct mutagen. Mutagenicity in the presence of S9 is attributed mainly to amine metabolism, Hydrophobicity has only a limited effect on this activity, whereas an unexpected positive correlation is found with electrochemical oxidation potential. The influence of reciprocal electronic delocalization effects of nitro and amino groups, through the modulation of the ultimate mutagenic species (nitrenium ion) reactivity, is also discussed.