Lowering of 5-nitroimidazole's mutagenicity: towards optimal antiparasitic pharmacophore.
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.
Crozet
Maxime D
MD
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.
Botta
Céline
C
Gasquet
Monique
M
Curti
Christophe
C
Rémusat
Vincent
V
Hutter
Sébastien
S
Chapelle
Olivier
O
Azas
Nadine
N
De Méo
Michel
M
Vanelle
Patrice
P
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
D000977:Antiparasitic Agents; D007093:Imidazoles; D009593:Nitroimidazoles; C052587:4-nitroimidazole