ROLE OF CLASSICAL NITROREDUCTASE AND O-ACETYLTRANSFERASE ON THE MUTAGENICITY OF NIFURTIMOX AND 8 DERIVATIVES IN SALMONELLA-TYPHIMURIUM

This study investigates the mutagenicity of nifurtimox (NFX) a nd eight analogues in Solmonella typhimurium indicator strains that possess different revels of classical nitroreductase or O-acetyltransferase activities. The NFX analogues tested replace the 3-methyl-4-yl-tetrahydro-1,4-thiozine-1,l-dioxide group of the parent compound with the following other groups: indozol-1-yl (1G); pyrazol-1-yl (1B); benzimidazol-1-yl (1E); 1,2,4-triazol-4-yl (1D); 1-methyl-3-methylthiol-1 ,2,4-triazol-4-yl-5-thione (1l); 3,5-bis(methylthio)-1,2,4-triazol-4-yl (1H); 1-adamantyl (ADA); and 4,6-diphenylpyridin-1-yl-2-one (1K). In the genetic backgrounds of the standard Ames tester strains TA98 and TAIOO, these bacteria combine the L-arabinose resistance forward mutation assay (Ara test) with a deficiency or overproduction of either nitroreduction or O-acetylation. The Ara test revealed, in agreement with previous findings, important differences between TA98 and TA100 and demonstrated, moreover, that these genetic differences ore of significance in mutagenicity testing with nitrofuran compounds. The Ara test also indicated dissimilarities between the metabolic activation of NFX and its analogues, these compounds being classified in three different groups according to their mutagenicity toward strain BA14 (genetic background of TA98) and its derivatives. The first group included analogues (1G, 1E, 1I, and ADA) that showed similar mutagenic potency in all bacterial strains. These compounds are considered not to be substrates for both classical nitroreductase and O-acetyltransferase. The second group included compounds (analogues 1B and 1K, and the reference drug NFX) with increased mutagenicity toward the strain overproducing the classical nitro-reductase, and/or reduced mutagenicity toward the corresponding deficient bacteria. These compounds are considered to be activated by the classical nitroreductase. The third group (analogues 1D and 1H) was activated by bacterial O-acetyltransferase, and consequently showed increased and decreased mutagenicity with the particular overproducer or deficient bacterial strain, as compared to their isogenic parentals. Previous reports have pointed out interest in NFX analogue 1H os a promising candidate for the replacement of NFX. The present study further enhances the putative interest of compound 1H, based on the different metabolic activation pathway exhibited by this analogue as compared to the parental drug, NFX. (C) 1995 Wiley-Liss, Inc.