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

In the search for novel chemotypes with high sp character and activity against the human malaria parasite , a spiroindoline series was identified from a phenotypic high-throughput screening campaign. The spiroindoline hit displayed good activity against both drug-sensitive and multidrug-resistant 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 () with improved antiplasmodial activity, aqueous solubility, and microsomal metabolic stability. Data from additional parasitological profiling suggested that likely has a mode of action differing from that of the original spiroindoline hit. Compound showed excellent pharmacokinetics with efficacy being achieved in a humanized immunodeficient NSG mouse 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.