Synthesis and antiplasmodial activity of new indolone N-oxide derivatives.

Synthesis and antiplasmodial activity of new indolone N-oxide derivatives.

Journal of medicinal chemistry (2009-12-18)

Françoise Nepveu, 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

PMID20014857

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.

MATERIALS

Product Number

Brand

Product Description

V4629

Sigma-Aldrich

(±)-Verapamil hydrochloride, ≥99% (titration), powder