Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1 H,3′ H]-3-Aryl-2,2′-diindol-3′-ones

The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven diversely functionalized [1H,3′H]-3-substituted 2,2′-diindol-3′-ones were synthesized 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.