ABSTRACT
Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Imidazoles/chemistry , Malaria/drug therapy , Plasmodium falciparum/drug effects , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Humans , Malaria/enzymology , Malaria/parasitology , Models, Molecular , Molecular Docking Simulation , Plasmodium falciparum/enzymology , Protein Conformation , Protein Kinase Inhibitors/chemistryABSTRACT
Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.
Subject(s)
Antimalarials/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Imidazoles/pharmacology , Plasmodium falciparum/drug effects , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Cyclic GMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Imidazoles/chemical synthesis , Imidazoles/chemistry , Ligands , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
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 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.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
