Mutagenesis vol. 8 no. 3 pp. 183-188, 1993
© 1993 UK Environmental Mutagen Society/Oxford University Press
research-article |
Synthesis of a series of 5-nitro-(benzimidazoles and indoles) as novel antimycotics and evaluation as genotoxins in the Ames test
1Department of Pharmacology, University of Bologna Bologna Italy 2Department of Pharmaceutical Science, University of Bologna Bologna Italy 3Departmet of Chemistry ‘G.Ciamician’, University of Bologna Bologna Italy 4Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, USA
Nitrobenzimidazole and nitroindole derivatives related to oxkonazole and characterized by an oxyimink function have been synthesized as novel antimycotics and their mutagenic activity tested in Salmonella typhimurium strains TA100 and TA98 with and without an exogenous metabolizing system. TA98NR and TA98/1,8-DNP6 strains were employed to identify a specific metabolic reaction which governs the mutagenic potency. Active compounds are weak direct-acting mutagens. Only derivatives bearing a nitro group on the phenyl ring linked to the oxyiminic function and lacking halogenated substituents show mutagenic activity. Metabolism by bacterial enzyme systems is important to the expression of genotoxicity. The reductive activation of nitro-benzimidazoles and nitroindoles carried out by the ‘classical’ nitroreductase of Salmonella, which is defective in TA98NR, is required of mutagenicity. Similarly the O-acetyltransferase defective in TA98/1,8-DNP6 is required for the efficient production of the ultimate electrophilic nitrogen species,which react with DNA. The role of bacterial metabolism in mutation induction needs careful consideration to assess the potential risk to humans from nitrobenzimidazole and nitroindole antimycotics.
5To whom correspondence should be addressed at: Department of Pharmacology, University of Bologna, Via Irnerio 48, 1-40126 Bologna, Italy