Malaria is one of the most significant parasitic diseases in human history with approximately half of the world’s population at risk of infection.1 Infected individuals are estimated to total 219 million annually with 435,000 succumbing to the disease in 2016.2 Parasite resistance has developed against all available classes of antimalarials, including the current first-line treatment Artemisinin combination therapy (ACT).3 Therefore, an urgent need has arisen towards the development of antimalarials with novel mechanisms of action.
In collaboration with Janssen Pharmaceuticals and Medicines for Malaria Venture, we have undertaken a high-throughput screen of a large drug-like library against the asexual blood stage of Plasmodium falciparum and identified a number of hit chemical series. One of these series is the focus of the present studies and is mediated by an unknown mechanism of action with an interesting delayed parasite killing profile. Medicinal chemistry techniques have been used to identify a tight SAR and have generated a potent nanomolar inhibitor. These optimised hits are now being used for further mechanistic studies towards the identification of novel P. falciparum cellular targets.