title: Lowering of 5-nitroimidazole's mutagenicity: towards optimal antiparasitic pharmacophore.
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.
authors.affiliation: Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Université d'Aix-Marseille I, II et III-CNRS, UMR 6264: Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
authors.forename: Maxime D
authors.initials: MD
authors.lastname: Crozet
authors.forename: Céline
authors.initials: C
authors.lastname: Botta
authors.forename: Monique
authors.initials: M
authors.lastname: Gasquet
authors.forename: Christophe
authors.initials: C
authors.lastname: Curti
authors.forename: Vincent
authors.initials: V
authors.lastname: Rémusat
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.forename: Olivier
authors.initials: O
authors.lastname: Chapelle
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.forename: Michel
authors.initials: M
authors.lastname: De Méo
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007093:Imidazoles; D020128:Inhibitory Concentration 50; D009000:Monocytes / Q000187:drug effects; D009152:Mutagenicity Tests; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D012475:Salmonella / Q000187:drug effects; D013329:Structure-Activity Relationship; D014246:Trichomonas vaginalis / Q000187:drug effects
chemical_list: D000977:Antiparasitic Agents; D007093:Imidazoles; D009593:Nitroimidazoles; C052587:4-nitroimidazole