The covalent PfCLK3 inhibitor showed extended parasiticidal potency in the nanomolar range, as well as significantly improved selectivity over the human kinome and a more favourable cell viability profile in HepG2 cells when compared to the parent molecule TCMDC-135051 1. We conclude that a covalent binding mechanism for protein kinase inhibitors targeting essential malarial protein kinases could provide the pharmacodynamic and parasiticidal properties desired in a strategy for the development of a single dose cure for malaria.