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

One of the attractive properties
of artemisinins is 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 falciparum to artemisinin. This emerging
artemisinin resistance threatens to undermine the effectiveness of
antimalarial combination therapies. Herein, we describe the medicinal
chemistry efforts 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 asexual blood stages that cause disease, and activity against
gametocyte activation that is required for transmission. Furthermore,
we confirm that selective PKG inhibitors have a slow speed of kill,
while chemoproteomic analysis suggests for the first time serine/arginine
protein kinase 2 (SRPK2) targeting as a novel strategy for developing
antimalarial compounds with extremely fast-killing properties.