Synthesis and antiplasmodial activity of new indolone N-oxide derivatives

  • J Med Chem. 2010 Jan 28;53(2):699-714. doi: 10.1021/jm901300d.
Françoise Nepveu  1 ,  Sothea Kim ,  Jeremie Boyer ,  Olivier Chatriant ,  Hany Ibrahim ,  Karine Reybier ,  Marie-Carmen Monje ,  Severine Chevalley ,  Pierre Perio ,  Barbora H Lajoie ,  Jalloul Bouajila ,  Eric Deharo ,  Michel Sauvain ,  Rachida Tahar ,  Leonardo Basco ,  Antonella Pantaleo ,  Francesco Turini ,  Paolo Arese ,  Alexis Valentin ,  Eloise Thompson ,  Livia Vivas ,  Serge Petit ,  Jean-Pierre Nallet
Affiliations
  • 1. Université de Toulouse, UPS, UMR 152 (Laboratoire de Pharmacochimie des Substances Naturelles et Pharmacophores Redox), F-31062 Toulouse cedex 9, France. [email protected]
PMID: 20014857 DOI: 10.1021/jm901300d
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.