Influence of nitroreductase and O-acetyltransferase on the mutagenicity ofsubstituted nitrobenzothiophenamines in Salmonella typhimurium

The mutagenic activity of 17 substituted (aryl)(2-nitrobenzo[b]thiophen-3yl )amine has been evaluated in the Ames test with different isogenic strains of Salmonella typhimurium, that varied in their expression of nitroreductas e and O-acetyltransferase. Active derivatives induced frameshift mutations in TA98 strain, and differences in the chemical structure resulted in up to 15-fold changes in mutagenic activity. The non-mutagenic compounds are the unsubstituted parent compound and derivatives with pam-chloro, para-fluoro , para-diethylamino, meta-bromo and para-dimethylamino groups. They do not show any activity even in strains with higher level of nitroreductase or O- acetyltransferase. The addition of S9 fraction decreases the mutagenic pote ntial or gives comparable results to those obtained without metabolic activ ation. For electron-donating substituents, the meta-isomers display the gre atest mutagenic potency, whereas the transfer of the group to the para-posi tion leads to less active or unactive molecules. All active nitrobenzothiop henes are substrates for bacterial nitroreductase and O-acetyltransferase, as shown by the reduced mutagenicity in the deficient strains and increased mutagenicity in the corresponding overproducing bacteria. Previous reports have pointed out interest in nitrothiophene analogues with para-chloro, an d para-fluoro substituents as promising anti-inflammatory drugs. The presen t study further enhances the putative interest in these derivatives, based on absence of mutagenicity. (C) 1999 Elsevier Science Ireland Ltd. All righ ts reserved.