Synthesis and antiplasmodial activity of new indolone N-oxide derivatives.
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.
Nepveu
Françoise
F
Université de Toulouse, UPS, UMR 152 (Laboratoire de Pharmacochimie des Substances Naturelles et Pharmacophores Redox), F-31062 Toulouse cedex 9, France. nepveu@cict.fr
Kim
Sothea
S
Boyer
Jeremie
J
Chatriant
Olivier
O
Ibrahim
Hany
H
Reybier
Karine
K
Monje
Marie-Carmen
MC
Chevalley
Severine
S
Perio
Pierre
P
Lajoie
Barbora H
BH
Bouajila
Jalloul
J
Deharo
Eric
E
Sauvain
Michel
M
Tahar
Rachida
R
Basco
Leonardo
L
Pantaleo
Antonella
A
Turini
Francesco
F
Arese
Paolo
P
Valentin
Alexis
A
Thompson
Eloise
E
Vivas
Livia
L
Petit
Serge
S
Nallet
Jean-Pierre
JP
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
D000962:Antimalarials; D007211:Indoles; D010087:Oxides