Lowering of 5-nitroimidazole's mutagenicity: towards optimal antiparasitic pharmacophore.

Maxime D Crozet, Céline Botta, Monique Gasquet, Christophe Curti, Vincent Rémusat, Sébastien Hutter, Olivier Chapelle, Nadine Azas, Michel De Méo, Patrice Vanelle

Index: Eur. J. Med. Chem. 44(2) , 653-9, (2009)

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Abstract

To improve the antiparasitic pharmacophore, 20 5-nitroimidazoles bearing an arylsulfonylmethyl group were prepared from commercial imidazoles. The antiparasitic activity of these molecules was assessed against Trichomonas vaginalis, the in vitro cytotoxicity was evaluated on human monocytes and the mutagenicity was determined by the Salmonella mutagenicity assay. All IC(50) on T. vaginalis were below the one of metronidazole. The determination of the specificity indexes (SIs), defined as the ratios of the cytotoxic activity and the antitrichomonas activity, indicated that 11 derivatives had a SI over the one of metronidazole. Molecules, bearing an additional methyl group on the 2-position, showed a lower mutagenicity than metronidazole. Moreover, three derivatives were characterized by a low mutagenicity and an efficient antitrichomonas activity.