1. Synthesis and Antiplasmodial Activity of New Indolone N-Oxide Derivatives
- Author
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Karine Reybier, Francesco Turini, Pierre Perio, Hany Ibrahim, Eloise Thompson, Michel Sauvain, Marie-Carmen Monje, Leonardo K. Basco, Serge Petit, Séverine Chevalley, Jean-Pierre Nallet, Sothea Kim, Antonella Pantaleo, Paolo Arese, Barbora Lajoie, Olivier Chatriant, Alexis Valentin, Jeremie Boyer, Rachida Tahar, Françoise Nepveu, Jalloul Bouajila, Eric Deharo, Livia Vivas, Institut de Recherche pour le Développement - IRD (FRANCE), and Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
- Subjects
Indoles ,Plasmodium berghei ,Stereochemistry ,Plasmodium falciparum ,Biochimie, Biologie Moléculaire ,Drug Resistance ,Parasitemia ,Chemical synthesis ,Antimalarials ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,IndoloneN-Oxide Derivatives ,In vivo ,Cell Line, Tumor ,parasitic diseases ,Drug Discovery ,Animals ,Humans ,Cytotoxicity ,IC50 ,chemistry.chemical_classification ,biology ,Chemistry ,Aromatic amine ,Oxides ,biology.organism_classification ,In vitro ,Antiplasmodial Activity ,Molecular Medicine - Abstract
A series of 66 new indolone-N-oxide derivatives was synthesized with three different methods. Compounds were evaluated for in vitro activity against CQ-sensitive (3D7), CQ-resistant (FcB1), and CQ and pyrimethamine cross-resistant (K1) strains of Plasmodium falciparum (P.f.), as well as for cytotoxic concentration (CC(50)) on MCF7 and KB human tumor cell lines. Compound 26 (5-methoxy-indolone-N-oxide analogue) had the most potent antiplasmodial activity in vitro (3 nM on FcB1 and = 1.7 nM on 3D7) with a very satisfactory selectivity index (CC(50) MCF7/IC(50) FcB1: 14623; CC(50) KB/IC(50) 3D7: 198823). In in vivo experiments, compound 1 (dioxymethylene derivatives of the indolone-N-oxide) showed the best antiplasmodial activity against Plasmodium berghei, 62% inhibition of the parasitaemia at 30 mg/kg/day.
- Published
- 2009