title: Restricted bioreductive metabolism of a nitroimidazole-thiadiazole derivative with curative action in experimental Trypanosoma cruzi infections.
abstract: The bioreductive activation of megazol [2-amino-5(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole] promoted by ferredoxin: NADP+ oxidoreductase, rat liver microsomes and cellular fractions of Trypanosoma cruzi, Y strain, was investigated. Direct ESR detection and characterization by computer simulation of the megazol nitro anion radical were possible in the presence of NADPH and ferredoxin: NADP+ oxidoreductase under anaerobic conditions. By contrast, the megazol nitro anion radical was not detected in the presence of either rat liver microsomes or cellular fractions of T. cruzi under conditions where the corresponding nifurtimox anion radical was observed. The inefficiency of rat liver microsomes in catalyzing megazol reduction was also attested by visible light absorption spectroscopy. In the presence of cellular fractions of T. cruzi supplemented with NAD(P)H, megazol marginally affected oxygen consumption and decreased the yield of oxyradicals that can be spin-trapped with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Our results indicate a restricted bioreductive metabolism of megazol and suggest that its trypanocidal activity is unrelated to a redox-cycling process.
authors.affiliation: Department of Biochemistry, Universidade de São Paulo, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: Tsuhako
authors.forename: M J
authors.initials: MJ
authors.lastname: Alves
authors.forename: W
authors.initials: W
authors.lastname: Colli
authors.forename: Z
authors.initials: Z
authors.lastname: Brener
authors.forename: O
authors.initials: O
authors.lastname: Augusto
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D005288:Ferredoxins / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009547:Nifurtimox / Q000378:metabolism*; D009581:Nitrofurans / Q000378:metabolism*; D009593:Nitroimidazoles / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D013347:Subcellular Fractions; D013830:Thiadiazoles / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000378:metabolism*
chemical_list: D005288:Ferredoxins; D009581:Nitrofurans; D009593:Nitroimidazoles; D013830:Thiadiazoles; C013378:megazol; D009547:Nifurtimox; C009999:benzonidazole