One-electron reduction is commonly used in organic chemistry for the formation of radicals by the stepwise transfer of one or two electrons from a donor to an organic substrate. Besides metallic reagents, single-electron reducers based on neutral organic molecules have emerged as an attractive novel source of reducing electrons. The past 20 years have seen the blossoming of a particular class of organic reducing agents, the electron-rich olefins, and their application in organic synthesis. This Review gives an overview of the different types of organic donors and their specific characteristics in organic transformations.

Metronidazole (Mz)-resistant Giardia and Trichomonas were inhibited by 1 of 30 new 5-nitroimidazole drugs.Another five drugs were effective against some but not all of the Mz-resistant parasites. This study provides the incentive for the continued design of 5-nitroimidazole drugs to bypass cross-resistance among established 5-nitromidazole antiparasitic drugs.Metronidazole (Mz) and a related 5-nitroimidazole, tinidazole, are the only drugs recommended for the treatment of trichomoniasis and are the most-prescribed drugs for the treatment of giardiasis. However, clinical resistance to these drugs has been well documented; and in the event of overt clinical resistance to Mz in trichomonads, there is no alternative for treatment, when one keeps in mind the documented crossresistance between the currently used 5-nitroimidazole drugs and their worldwide availability (7,8,18,23). Some success has been obtained with quinacrine and albendazole in combination with Mz in cases of giardiasis treatment failures (23). On the positive side, a great deal of flexibility is offered by the side chains attached to the imidazole ring structure that bear the all important nitro group (17).The mechanisms of Mz resistance in Giardia and Trichomonas have been well studied in laboratory-induced resistance (18). It occurs by down-regulation of pathways, especially the enzyme pyruvate:ferredoxin oxidoreductase (PFOR) and ferredoxin (Fd) pathway, that activate Mz to its toxic radical state. The PFOR-Fd couple has an electron potential sufficiently low to activate Mz, while no such electron couple is present in the mammalian host (9). In the laboratory we see a threefold down-regulation of PFOR activity in Mz-resistant (Mz r ) Giardia duodenalis (14), and in highly Mz r Trichomonas vaginalis the activity of the hydrogenosome organelle is downregulated such that there is no detectable PFOR or Fd expression (4,11,18). Thus, Mz is not activated to its toxic radical state in these cells. On the other hand, it is well documented that clinically Mz r T. vaginalis strains do not have down-regulated hydrogenosomes, and the mechanism of Mz resistance in these cells is not understood (8).Previously, we showed that some 5-nitroimidazole derivatives were significantly more effective antiprotozoal agents (based on in vitro molar drug concentrations) than Mz against Mz-susceptible (Mz s ) parasites but were not as effective against Mz r parasites (17). Given the impetus for the development of 5-nitroimidazole drugs that vary markedly in their efficacies (both positively and negatively), we tested 30 new 5-nitroimidazoles in our anaerobic drug susceptibility screening assay (16) for their efficacies against T. vaginalis and G. duodenalis, with the focus on laboratory-derived Mz r (Mz rl ) lines and clinical isolates derived from patients with treatment failures.Parasites were cultured axenically in anaerobic TYI-S-33 (6), which was modified as described previously (16 All new 5-nitroimidazole compounds (Fig. 1) were identified by spectral data, purified b...

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The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID90 values around 100 μM (MTR-susceptible isolates typically have an ID90 of 5–12.8 μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells.

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The efficacies of 12 5-nitroimidazole compounds and 1 previously described lactam-substituted nitroimidazole with antiparasitic activity, synthesized via SRN1 and subsequent reactions, were assayed against the protozoan parasites Giardia duodenalis, Trichomonas vaginalis, andEntamoeba histolytica. Two metronidazole-sensitive lines and two metronidazole-resistant lines of Giardia and one line each of metronidazole-sensitive and -resistantTrichomonas were tested. All except one of the compounds were as effective or more effective than metronidazole againstGiardia and Trichomonas, but none was as effective overall as the previously described 2-lactam-substituted 5-nitroimidazole. None of the compounds was markedly more effective than metronidazole against Entamoeba. Significant cross-resistance between most of the drugs tested and metronidazole was evident among metronidazole-resistant lines of Giardia andTrichomonas. However, some drugs were lethal to metronidazole-resistant Giardia and had minimum lethal concentrations similar to that of metronidazole for drug-susceptible parasites. This study emphasizes the potential in developing new nitroimidazole drugs which are more effective than metronidazole and which may prove to be useful clinical alternatives to metronidazole.

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