Enzymatic reduction studies of nitroheterocycles

The nitroimidazole derivative Megazol is a highly active compound used agai nst several strains of Trypanosoma cruzi, the causative agent of Chagas' di sease (American trypanomiasis). With the aim of gaining an insight into the probable mode of action, the interaction of Megazol with different redox e nzymes was studied in comparison to that of Nifurtimox and Metronidazole. T he three nitroaromatic compounds are reduced by L-lactate cytochrome c-redu ctase, adrenodoxin reductase, and NADPH:cytochrome P-450 reductase (EC 1.6. 2.4), the efficiencies of the enzymatic reductions being roughly related to the reduction potentials of these pseudo-substrates. As the enzyme respons ible for the reduction of Megazol within the parasite has not yet been iden tified, the nitroimidazole was assayed with T. cruzi lipoamide dehydrogenas e and trypanothione reductase. Megazol did not inhibit the physiological re actions but proved to Or a weak substrate of both flavoenzymes. The single electron reduction of the compound by NADPH:cytochrome P-450 reductase, by rat liver as well as by trypanosome microsomes was confirmed by ESR experim ents. As shown here, Megazol interferes with the oxygen metabolism of the p arasite, but its extra activity when compared to Nifurtimox may be related to other features not yet identified. BIOCHEM PHARMACOL 57;5:549-557, 1999. (C) 1999 Elsevier Science Inc.