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To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the  Plasmodium falciparum  cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC 50  of 160 pM in a PfPKG kinase assay and inhibits  P. falciparum  blood stage proliferation in vitro with an EC 50  of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a  P. falciparum  SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature  P. falciparum  gametocytes to  Anopheles stephensi  mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission