Development of Chemical Entities Endowed with Potent Fast- Killing Properties against Plasmodium falciparum Malaria Parasites

One of the attractive properties of artemisininsis their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparumto artemisinin. This emerging artemisininresistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistryefforts focused on a cGMP-dependent protein kinase(PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexualblood stages that cause disease, and activity against gametocyteactivation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomicanalysis suggests for the first time serine/arginine prot...