ABSTRACT
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.
Subject(s)
1-Phosphatidylinositol 4-Kinase , Antimalarials , Hemeproteins , Naphthyridines , Plasmodium falciparum , Zebrafish , Plasmodium falciparum/drug effects , Animals , Naphthyridines/pharmacology , Naphthyridines/chemistry , Naphthyridines/chemical synthesis , Naphthyridines/therapeutic use , Antimalarials/pharmacology , Antimalarials/chemistry , Antimalarials/chemical synthesis , 1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , 1-Phosphatidylinositol 4-Kinase/metabolism , Humans , Structure-Activity Relationship , Hemeproteins/antagonists & inhibitors , Hemeproteins/metabolism , Mice , Rats , Malaria, Falciparum/drug therapy , Male , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesisABSTRACT
We recently reported a series of compounds for a solubility-driven optimization campaign of antitrypanosomal compounds. Extending a parasite-hopping approach to the series, a subset of compounds from this library has been cross-screened for activity against the metazoan flatworm parasite, Schistosoma mansoni. This study reports the identification and preliminary development of several potently bioactive compounds against adult schistosomes, one or more of which represent promising leads for further assessment and optimization.
ABSTRACT
Potential drug molecules are often discarded due to poor physicochemical properties and pharmacokinetic profiles. As such, research into the use of multicomponent crystal systems (such as salts and co-crystals) is currently being conducted with the aim of improving the properties of the molecule, without altering the bioactivity of the drug. Although numerous studies have been performed on a wide variety of drug molecules, research with antimalarial drug molecules seems to have been neglected. With many of the current drugs becoming inactive due to resistance, there is an urgent need to find effective drugs with good pharmacokinetic profiles. The objective of this review is therefore to determine the extent to which multicomponent crystal systems have been used in antimalarial chemotherapy and whether this method provides a viable alternative to discarding potential drug candidates.
