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Antimalarial drug resistance compels the quest for new compounds that target alternative pathways to current drugs. The  Plasmodium  cyclic GMP-dependent protein kinase (PKG) has essential functions in all of the major life cycle developmental stages. An imidazopyridine PKG inhibitor scaffold was previously shown to clear  P. falciparum  infection in a rodent model  in vivo  and blocked transmission to mosquitoes providing proof of concept for this target. To find new classes of PKG inhibitors to serve as alternative chemical starting points, we performed a high-throughput screen of the GSK Full Diversity Collection using recombinant  P. falciparum  PKG. We developed a robust enzymatic assay in a 1536-well plate format. Promising compounds were then tested for activity against  P. falciparum  asexual blood stage growth, selectivity and cytotoxicity. By using a scoring system we selected the 66 most promising PKG inhibitors (comprising nine clusters and seven singletons). Among these, thiazoles were the most potent scaffold with mid-nanomolar activity on  P. falciparum  blood stage and gamete development. Using Kinobeads profiling we identified additional  P. falciparum  protein kinases targeted by the thiazoles that mediate a faster speed of the kill than PKG-selective compounds. This scaffold represents a promising starting point to develop a new antimalarial.

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High-throughput screening of the Plasmodium falciparum cGMP-dependent protein kinase identified a thiazole scaffold which kills erythrocytic and sexual stage parasites