64570-18-9Relevant academic research and scientific papers
Cross-resistance to nitro drugs and implications for treatment of human african trypanosomiasis
Sokolova, Antoaneta Y.,Wyllie, Susan,Patterson, Stephen,Oza, Sandra L.,Read, Kevin D.,Fairlamb, Alan H.
experimental part, p. 2893 - 2900 (2011/10/05)
The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (～27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy. Copyright
Chemotherapeutically active nitro compounds. 4,5-Nitroimidazoles (part III)
Winkelmann,Raether
, p. 739 - 749 (2007/10/05)
More than 100 1-methyl-5-nitroimidazoles substituted in the 2-position via an oxymethyl group were synthesized and their structure-activity relationship toward various protozoa was investigated. Among the derivatives substituted with an aromatic radical there are most of the compounds which are highly effective against trichomonads; 9 preparations are superior to tinidazole and 29 are superior to metronidazole in mice infected with Trichomonas fetus and 9 compounds exhibit a better effect than metronidazole in golden hamsters intrahepatically infected with Entamoeba histolytica. In the same series one dialkylamino-acetamide derivative shows excellent trypanocidal activity in the NMRI mouse, but this effect is limited to Trypanosoma brucei; 12 preparations developed a trypanocidal effect only after relatively high doses; their range of efficacy included Trypanosoma cruzi, among others, after repeated treatment. Of the carboxyl acid, carbamic acid and sulphonic acid esters synthesized, only the already known group of carbamic acid esters possess a pronounced antiprotozoal effect. Among the preparations substituted with a heterocyclic radical some of the pyridine derivatives proved to have distinct trichomonacidal activity. The influence of the type of substitution and the stability of the C-X bond in 2-substituted 5-nitroimidazoles of all compounds synthesized so far (I-III, 4th report) are discussed in 2 tables.
1-Alkyl-2-(phenoxymethyl)-5-nitro-imidazoles and process for their manufacture
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, (2008/06/13)
1-Alkyl-2-(phenoxymethyl)-5-nitro-imidazoles are described as well as a process for their manufacture. The compounds are active against trichomonads and amoebae and are especially suitable for the treatment of Fluor genitalis.
