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.
Synthesis and Antiplasmodial Activity of New Indolone N-Oxide Derivatives / Nepveu, F; Kim, S; Boyer, J; Chatriant, O; Ibrahim, H; Reybier, K; Monje, Mc; Chevalley, S; Perio, P; Lajoie, Bh; Bouajila, J; Deharo, E; Sauvain, M; Tahar, R; Basco, L; Pantaleo, Antonella; Turrini, F; Arese, P; Valentin, A; Thompson, E; Vivas, L; Petit, S; Nallet, Jp. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:(2010), pp. 699-714. [10.1021/jm901300d]