MECHANISM OF GENOTOXICITY AND ELECTRON-DENSITY DISTRIBUTION BY NMR OF5-NITRO-3-THIOPHENECARBOXAMIDES, A NOVEL GROUP OF DIRECT-ACTING MUTAGENS IN SALMONELLA-TYPHIMURIUM

The mutagenic activity of 23 5-nitro-3-thiophenecarboxanilides and of 5-nitro-3-thiophenecarboxamide, the prototype, (NTCAs) have been evalu ated in the Ames test on Salmonella typhimurium strains TA100 ad TA98 with and without metabolic activation. Effects of different substituen ts (electron-donating and electron-withdrawing) were studied to evalua te structural features that affect the metabolism and the bacterial mu tagenic potency. All the derivatives were direct-acting mutagens, the mutagenic potency ranging from 0.7 to 142 revertants (rev.)/nmol in TA 100 and from 0.09 to 68 rev./nmol in TA98 strain. Results obtained wit h strains TA98NR and TA98/1,8-DNP6 indicated that the mutagenic activi ty was largely dependent on bacterial nitroreductase, whereas the O-ac etylation step was not critical for mutagenic potency. Superoxide (O2- .) and hydroxyl (OH.) scavengers as well as other radical scavengers a nd enzymes inhibited NTCAs mutagenicity to different extents. In parti cular, O2-. seemed to be involved in NTCAs mutagenicity, showing a fre e radical pathway for NTCA metabolism. [H-1]- and [C-13]NMR data indic ated that the effects of different substituents on genotoxicity are pr obably not exerted on the electron density distribution. The importanc e of factors such as extent of nitration, reduction potential, orienta tion of nitrosubstituent and planarity of the molecule are discussed.