article · Journal of Medicinal Chemistry
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously recognised as inhibitors of Plasmodium falciparum phosphatidylinositol-4-kinase beta (PI4K), have led to the identification of modified 1,5-naphthyridines with basic groups at the 8-position. While retaining parasite PI4K inhibition, these molecules switched their primary mechanism to inhibiting hemozoin formation within the host haemoglobin degradation pathway. Importantly, the compounds demonstrated minimal off-target activity against human phosphoinositide, MINK1, and MAP4K kinases, which were previously linked to toxicities found in the clinical candidate MMV390048. A leading compound proved effective against both field isolates and resistant laboratory strains of the malaria parasite. It also displayed in vivo efficacy at a single oral dose in a humanised mouse infection model, showed no teratogenicity in zebrafish embryos, and presents a low predicted human dose.
Malaria remains a major global health challenge as parasites continually develop resistance to current therapies. These findings highlight a series of compounds that fight malaria through two distinct mechanisms simultaneously while reducing harmful off-target side effects seen in earlier drug candidates. This dual action helps address drug-resistant strains without compromising safety.
This research provides an early-stage drug discovery asset for pharmaceutical developers and translational researchers working on antimalarial therapies. By demonstrating in vivo efficacy in mouse models, lack of teratogenicity in zebrafish, and effectiveness against resistant field isolates, the series represents an applied discovery programme with potential to yield a formal preclinical candidate.
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Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of <i>Plasmodium falciparum</i> (<i>Pf</i>) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained <i>Plasmodium</i> 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 <i>Pf</i>PI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of <i>Pf</i>. 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.
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DOI: 10.1021/acs.jmedchem.4c01154
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