RÉSUMÉ
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.
Sujet(s)
1-Phosphatidylinositol 4-kinase , Antipaludiques , Hémoprotéines , Naphtyridines , Plasmodium falciparum , Danio zébré , Plasmodium falciparum/effets des médicaments et des substances chimiques , Animaux , Naphtyridines/pharmacologie , Naphtyridines/composition chimique , Naphtyridines/synthèse chimique , Naphtyridines/usage thérapeutique , Antipaludiques/pharmacologie , Antipaludiques/composition chimique , Antipaludiques/synthèse chimique , 1-Phosphatidylinositol 4-kinase/antagonistes et inhibiteurs , 1-Phosphatidylinositol 4-kinase/métabolisme , Humains , Relation structure-activité , Hémoprotéines/antagonistes et inhibiteurs , Hémoprotéines/métabolisme , Souris , Rats , Paludisme à Plasmodium falciparum/traitement médicamenteux , Mâle , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/synthèse chimiqueRÉSUMÉ
The biomineral haemozoin, or its synthetic analogue ß-haematin (ßH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known ßH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of ßH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of ßH and whole cell parasite growth.
