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

ABSTRACT: 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 IC₅₀ of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC₅₀ 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 o

SUBMITTER: Baker DA 

PROVIDER: S-EPMC5585294 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature