Mechanism of genotoxicity and electron density distribution by NMR of 5-nitro-3-thiophenecarboxamides, a novel group of direct-acting mutagens in Salmonella typhimurium.

ABSTRACT

The mutagenic activity of 23 5-nitro-3-thiophenecarboxanilides and of 5-nitro-3-thiophenecarboxamide, the prototype, (NTCAs) have been evaluated in the Ames test on Salmonella typhimurium strains TA100 ad TA98 with and without metabolic activation. Effects of different substituents (electron-donating and electron-withdrawing) were studied to evaluate structural features that affect the metabolism and the bacterial mutagenic potency. All the derivatives were direct-acting mutagens, the mutagenic potency ranging from 0.7 to 142 revertants (rev.)/nmol in TA100 and from 0.09 to 68 rev./nmol in TA98 strain. Results obtained with strains TA98NR and TA98/1,8-DNP6 indicated that the mutagenic activity was largely dependent on bacterial nitroreductase, whereas the O-acetylation step was not critical for mutagenic potency. Superoxide (O2-.) and hydroxyl (OH.) scavengers as well as other radical scavengers and enzymes inhibited NTCAs mutagenicity to different extents. In particular, O2-. seemed to be involved in NTCAs mutagenicity, showing a free radical pathway for NTCA metabolism. [1H]- and [13C]NMR data indicated that the effects of different substituents on genotoxicity are probably not exerted on the electron density distribution. The importance of factors such as extent of nitration, reduction potential, orientation of nitrosubstituent and planarity of the molecule are discussed.