STRUCTURE-ACTIVITY-RELATIONSHIPS WITHIN VARIOUS SERIES OF P-PHENYLENEDIAMINE DERIVATIVES

The mutagenicity of 20 p-phenylenediamine derivatives has been investi gated in Salmonella typhimurium. Tests were performed in the presence and in the absence of Aroclor 1254-induced liver S9 fractions derived from male Wistar rats. Among five series of compounds tested, nitro-p- phenylenediamines with substituents at the Cg position (4-amino-3-nitr o-6-methylaniline; 4-amino-3-nitro-6-methoxyaniline; 4-amino-3-nitro-6 -fluoroaniline; 4-amino-3-nitro-6-chloroaniline; and 4-amino-3-nitro-i sopropylaniline) were the most mutagenic. In all cases, the compounds were less mutagenic in the absence of S9 than in its presence, but thr ee of the five compounds (the methoxy, fluoro, and chloro derivatives) were still mutagenic without the metabolic activation system. In cont rast to the mutagenicity of the C-6-substituted compounds, the mutagen icity of analogues with substituents on the C-5 position (4-amino-3-ni tro-5-beta-hydroxypropyraniline; 4-amino-3-nitro-5-isopropylaniline; 4 -amino-3-nitro-5-methylaniline; and 4-amino-3-nitro-5-beta-hydroxyethy laniline) was abolished or reduced. A dramatic reduction in mutagenic activity was also achieved when two methyl groups, instead of one, wer e added to 4-amino-3-nitroaniline. For example, 4-amino-3-nitro-5,6-di methylaniline and 4-amino-3-nitro-2,5-dimethylaniline were only weakly mutagenic, and 4-amino-3-nitro-2,6-dimethylaniline was nonmutagenic. Monocyclic compounds such as 4-amino-2,6-dimethylaniline; 4-amino-5,6- dimethylaniline; 4-amino-2-methoxy-3,5-dimethylaniline, and 4-amino-2, 3,5,6-tetramethylaniline were all nonmutagenic in Salmonella typhimuri um. The compound 4-amino-2,5-dimethylaniline was weakly mutagenic or n onmutagenic, whereas 4-amino-2,5-dimethoxyaniline was mutagenic. It ap pears that the mutagenic activity or inactivity of these compounds dep ends on both the chemical groups present and their positions in the mo lecule. In this context, it seems that the presence of the NO2 group a nd the nature of the substituent groups at the C-5 and C-6 positions o n the benzene ring are crucial factors in determining the mutagenicity of these compounds.