Amino derivatives of indolone-N-oxide: Preparation and antiplasmodial properties

• Synthesis of twelve novel amino-indolone-N-oxide derivatives.
• All compounds were evaluated for in vitro antimalarial activity and cytotoxicity.
• Half of them had IC50 values <150 nM.
• The cytotoxicity of the amino derivatives of indolone-N-oxide was relatively low.

There is an urgent need for new antimalarial drugs with novel mechanisms of action on novel targets. Indolone-N-oxides (INODs) display antimalarial properties in vitro and in vivo, but identified leads such as 6-(4-chloro-phenyl)-5-oxy-[1,3]dioxolo[4,5-f]indol-7-one 1, suffer from very poor aqueous solubility. In this study, structural modifications have been made by introducing various amino and bulky groups to produce sufficiently water soluble and active compounds for further pharmacological and pharmacokinetic studies. We report here the preparation of twelve novel amino derivatives and their antiplasmodial activities including those of two other structurally known compounds. The 5-methoxy-2-(4-morpholin-4-yl-phenyl)-1-oxy-indol-3-one, 9, has the highest antiplasmodial activity in vitro (IC50 = 6.5 nM; FcB1 strain) and selectivity index (SI (CC50 MCF7/IC50 FcB1) = 4538.5). The 6-amino-2-(4-chloro-phenyl)-1-oxy-indol-3-one, 14, (IC50 = 183 nM; SI = 60), is an excellent candidate for further mechanistic studies. Indeed, this is structurally the closest analogue to the current lead, 1, bearing an NH2 group at R2 offering possibilities for functionalization and labeling.

A series of original amino-indolone-N-oxides was synthesized via the nitro-alkyne cycloisomerization of o-alkynylnitrobenzenes and was evaluated for in vitro activity against chloroquine-resistant strains of Plasmodium falciparum.Figure optionsDownload as PowerPoint slide