norketotifen and Malaria

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

Topics: Animals; Antimalarials; Female; Humans; Inhibitory Concentration 50; Ketotifen; Liver; Malaria; Malaria, Falciparum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Prodrugs

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

Topics: Animals; Antimalarials; Cell Line, Tumor; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistance; Erythrocytes; Humans; Imidazoles; Liver; Malaria; Mice; Mice, Inbred BALB C; Molecular Structure; Piperazines; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Polymorphism, Single Nucleotide; Protozoan Proteins; Random Allocation; Small Molecule Libraries; Sporozoites