title: Synthesis and antiplasmodial activity of new indolone N-oxide derivatives.
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.
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire de Pharmacochimie des Substances Naturelles et Pharmacophores Redox), F-31062 Toulouse cedex 9, France. nepveu@cict.fr
authors.forename: Françoise
authors.initials: F
authors.lastname: Nepveu
authors.forename: Sothea
authors.initials: S
authors.lastname: Kim
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boyer
authors.forename: Olivier
authors.initials: O
authors.lastname: Chatriant
authors.forename: Hany
authors.initials: H
authors.lastname: Ibrahim
authors.forename: Karine
authors.initials: K
authors.lastname: Reybier
authors.forename: Marie-Carmen
authors.initials: MC
authors.lastname: Monje
authors.forename: Severine
authors.initials: S
authors.lastname: Chevalley
authors.forename: Pierre
authors.initials: P
authors.lastname: Perio
authors.forename: Barbora H
authors.initials: BH
authors.lastname: Lajoie
authors.forename: Jalloul
authors.initials: J
authors.lastname: Bouajila
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
authors.forename: Michel
authors.initials: M
authors.lastname: Sauvain
authors.forename: Rachida
authors.initials: R
authors.lastname: Tahar
authors.forename: Leonardo
authors.initials: L
authors.lastname: Basco
authors.forename: Antonella
authors.initials: A
authors.lastname: Pantaleo
authors.forename: Francesco
authors.initials: F
authors.lastname: Turini
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
authors.forename: Alexis
authors.initials: A
authors.lastname: Valentin
authors.forename: Eloise
authors.initials: E
authors.lastname: Thompson
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Serge
authors.initials: S
authors.lastname: Petit
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Nallet
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004351:Drug Resistance; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010087:Oxides / Q000138:chemical synthesis / Q000494:pharmacology; D018512:Parasitemia / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D007211:Indoles; D010087:Oxides