Metronidazole anion radicals

Fig. 3 Signal of metronidazole anion radicals generated by hydrogenosomes of T. vaginalis in the presence of 45 mM metronidazole, pyruvate, CoA, and ferredoxin (activity of PFOR). Recorded by EPR spectroscopy at 25 °C with 20 mW of microwave power, a frequency of 9.64 GHz, and a modulation amplitude of 0.19 mT. The hyperfine coupling constants were n0no2 = 1 565 mT, Hfl4 = 0.542 mT, and - 0.229 mT...

Fig. 4 Scheme of alternative pathway of metronidazole activation in hydrogenosomes of T. vaginalis the malate pathway. Electrons generated by hydrogenosomal malic enzyme (ME) reduce NAD+ to NADH, NADH dehydrogenase (NDH) recycles NADH and transfers electrons to ferredoxin (Fd) which, in a final step, donates electrons for metronidazole reduction. MTZ metronidazole, R-NO2" metronidazole anion radicals. Experimental conditions as in Fig. 3... 

Lloyd D, Pedersen JZ (1985) Metronidazole anion radical anion generation in vivo in Trichomonas vaginalis oxygen quenching is enhanced in a drug-resistant strain. J Gen Microbiol 131 87-92... 

Fig. 6 Scheme of futile cycling of metronidazole in the presence of oxygen. Nitro anion radicals are converted back to the inactive reoxidized form. By-products of this conversion are superoxide radicals... 

Flash photolysis of misonidazole, metronidazole, and nitrobenzothiazoles has been carried out in [1369-1371], Laser flash-photolysis (355 nm) allows to determine relatively stable anion-radicals of misonidazole and metronidazole in aqueous solutions [1370], Solvated electrons have been formed at harder irradiation, the result of which interaction with nitroimidazole molecules is generation of their radical anions [1372], The authors [1372] have also found that fluorescence intensity of metronidazole is about 20 times more than that of misonidazole in same conditions. Photochromic properties of benzothiazole derivatives containing nitro and methyl groups in the ortho positions with respect to each other were studied by flash photolysis [1371], The application of the thermodynamic approach to predict the kinetic stability of formed nitronic acids is limited owing to specific intramolecular interactions. The lifetime of photoinduced nitronic acid anions tends to increase with rise in the chemical shift of the methyl protons. The rate constants photoinduced nitronic acids and their anions increase as the CH3C-CN02 bond becomes longer [1371],... 

Considerable interest has been reported in the radiolytic reactions of radiosensitiz-ing nitroimidazoles such ns Metronidazole, 2-methyl-5-nitro-l//-imidazole-1-ethanol (52). Again loss of the nitro function as nitrite appears to be one of the principal events. The formation of nitrite from /-irradiation of the Ni(II) complex of the imidazole 52 arises by hydroxy radical attack to form the radical anion. This either eliminates nitrite or undergoes a four-electron reduction to a hydroxylamino derivative68,69. 

The mode of action of these nitroheterocycles is of interest. The nitroimidazoles are much more effective against anaerobic organisms than against aerobes. Indeed, low concentrations of oxygen reduce the effectiveness in vitro of metronidazole (33) against E. coli (81MI10803). This has been explained by the formation of the reactive radical anion (38),... 

The ESR spectra of radical ions of known radiosensitizers metronidazole, misonidazole, omidazole, and other nitroimidazoles have been investigated in the conditions of photolysis [856, 857], pulse radiolysis [849, 856, 858-865], and in the presence of other donors of free electrons [866-872], Radical anions of 2-nitroimi-dazole [849] and 4(5)-nitroimidazole [860] depending on medium pH can exist in three forms (Scheme 3.21) ... 

Moore E, ChigneU CF, Sik RH, Motten AG. Generation of radical anions from metronidazole, misonidazole and azathioprine by photoreduction in the presence of EDT A. Int J Radiat Biol 1986 50 885-891. 

As discussed for metronidazole, nifurtimox is thought to undergo reduction followed by oxidation and, in the process, generate ROS, such as the superoxide radical anion, hydrogen peroxide, and hydroxyl radical (Fig. 39.3) (5). These species are potent oxidants, producing oxidative stress that may produce damage to DNA and lipids that may affect cellular membranes. In addition, Henderson et al. (27) have reported that nifurtimox inhibits trypanothione reductase, which results in the inhibition of trypanothione formation (93% inhibition). Trypanothione is a critical protective enzyme found uniquely in trypanosomal parasites. 

There are only a few reports of antimicrobial activity of Ru(II) arene complexes. Tocher et al. [73] found that coordination of metronidazole in [(r -benzene)-RuCl2(metronidazole)j (21, Fig. 2.9) did not alter the electron affinity of metronidazole, but decreased the lifetime of the one-electron reduction product (the nitro radical anion) and increased the differential cytotoxicity towards E. coli grown under hypoxic conditions. 

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