Cell-Based Progression of Spiroindoline Phenotypic Hits Leads to the Identification of Compounds with Diverging Parasitological Profiles against the Human Malaria Parasite Plasmodium falciparum.

In the search for novel chemotypes with high sp3 character and activity against the human malaria parasite Plasmodium falciparum, a spiroindoline series was identified from a phenotypic high-throughput screening campaign. The spiroindoline hit 2 displayed good activity against both drug-sensitive and multidrug-resistant Plasmodium strains, making it an attractive starting point for hit-to-lead progression. Structure-activity relationship studies led to the identification of a novel pyridylspiroindoline frontrunner (50) with improved antiplasmodial activity, aqueous solubility, and microsomal metabolic stability. Data from additional parasitological profiling suggested that 50 likely has a mode of action differing from that of the original spiroindoline hit. Compound 50 showed excellent in vivo pharmacokinetics with efficacy being achieved in a humanized immunodeficient NSG mouse P. falciparum infection model. This provided a pharmacological proof-of-concept for this series, making it a valuable starting point for further optimization in the quest for novel antimalarial therapeutics.