Molecular Horizons PhD Exit Seminar

The design and synthesis of small-molecule inhibitors has long been at the forefront of modern drug discovery and medicinal chemistry efforts, however the inherent inefficiencies of the ‘traditional’ convergent approach have led to a growing appreciation of diversity-oriented synthesis as a means of rapidly exploring new chemical space. Stepwise divergence is not without its own drawbacks however (materials, time, money, sanity), and so the ability to convert simple molecules into highly-complex scaffolds in a single reaction is a powerful tool.

Cascade (or domino) reactions are the equivalent of chemical shortcuts, and offer the ability to perform multiple sequential reactions one after the other. Previous work in the Keller Research Group has demonstrated the ability for indigo dye (used throughout antiquity – now used to dye blue jeans) to undergo cascade reactions with allylic and propargylic bromides, generating a series of highly-functionalised and structurally-diverse heterocycles directly from indigo in one or two steps.

Throughout the course of this project, we sought to exploit indigo’s multi-faceted reactivity as a platform for the generation of new scaffolds inhibiting P. falciparum parasites in vitro. Leveraging the reactivity of a) terminally-substituted propargylic systems, b) strained-ring electrophiles, and c) functionalised organometallic nucleophiles, we gained access to a series of polycyclic heterocycles with sub-micromolar antiparasitic activity, permanently dyed a variety of laboratory equipment blue, and serendipitously discovered a new method for the bis-sulfonamidation of olefins. Primary in vitro screening of this compound library revealed submicromolar activity of several scaffolds against P. falciparum parasites, while exhibiting very low human cell toxicity (SI values up to >1500).