cgp-71683-a and Malaria

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

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.

Topics: Animals; Antimalarials; Cluster Analysis; Computational Biology; Drug Evaluation, Preclinical; Drug Resistance; Folic Acid Antagonists; Malaria; Models, Molecular; Parasites; Plasmodium falciparum; Reproducibility of Results; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase