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Chemotherapeutically acitve nitro compounds. 4. 5-Nitroimidazoles (Part III).

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 possesses 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.

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Chemotherapeutically active nitro compounds. 4. 5-Nitroimidazoles (Part I).

More than 135 new 2-methyl-5-nitroimidazoles substituted in 1-position and 1-methyl-5-nitroimidazoles substituted in 2-position were investigated for their activity against various protozoan species, in particular Entamoeba histolytica in the golden hamster, Trichomonas fetus, Trypanosoma brucei and T. cruzi in the NMRI mouse. Among the nitroimidazoles substituted in the 1-position only two preparations exhibited a similar effect as metronidazole preparations exhibited a similar effect as metronidazole against T. fetus. In the class of the nitroimidazoles substituted in the 2-position 16 compounds were as effective as metronidazole, 19 showed an effect superior to metronidazole, 1 was as good as tinidazole and 2 exhibited an activity superior to tinidazole against T. fetus. Only few compounds displayed any amoebicidal activity. Of the mono and bis-hydrazones of 1-methyl-5-nitroimidazole-2-aldehyde substituted in the 2-position 3 compounds had an amoebicidal effect 2 to 8 times stronger than that of metronidazole. Only few representatives of the 1-methyl-5-nitroimidazoles substituted in the 2-position produced a useful trypanocidal effect when given in relatively high doses. The structure-activity relationship of 5-nitroimidazole derivatives has been discussed.

Animals↗

Chemotherapeutically active nitro compounds. 4.5-Nitroimidazoles (Part II).

More than 170 1-methyl-5-nitroimidazoles substituted in the 2-position via an aminomethyl, thiomethyl, sulphinylmethyl or sulphonylmethyl group were synthesized and tested for their effect against various protozoa. In the NMRI mouse which had been i.p. infected with Trichomonas fetus 2 compounds showed an effect superior to that of tinidazole and 31 showed similarly good efficacy as that compound. In comparison with metronidazole 54 preparations proved to be distinctly more active, while 34 others lay in the range of efficacy of the standard compound. A large majority of the most active derivatives is substituted in the 2-position via a C--S bridge with heterocyclics, particularly with a pyridyl radical. An effect against Entamoeba histolytica in the intrahepatically infected golden hamster was observed much less often. Only 14 preparations developed a systemic effect comparable with that of metronidazole. In the NMRI mouse infected i.p. with Trypanosoma brucei or s.c. with T. cruzi parasitemia was clearly influenced by 11 compounds. With a few exceptions a trypanocidal effect against T. brucei occurred only at high doses. Only 3 compounds showed pronounced suppressive activity against blood forms of T. cruzi and only after prolonged treatment. The structure-activity relationship of the new 5-nitroimidazoles is discussed.

Animals↗