Desymmetrisation reactions of indigo with Grignard reagents for the synthesis of selective antiplasmodial [1H,3ꞌH]-3-aryl-2,2ꞌ-diindol-3ꞌ-ones.

Abstract

The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrisation of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven diversely-functionalised [1H,3ꞌH]-3-substituted-2,2ꞌ-diindol-3ꞌ-ones were synthesised by this methodology, with several showing submicromolar inhibition and exquisite selectivity against P. falciparum parasites (3D7 and Dd2 strains) in vitro. This work demonstrates the utility of indigo dye as a highly-versatile scaffold for the synthesis of structurally-diverse, bioactive heterocycles.