Antimalarial Imidazopyridines Incorporating an Intramolecular Hydrogen Bonding Motif: Medicinal Chemistry and Mechanistic Studies

[Image: see text] We previously identified a novel class of antimalarial benzimidazoles incorporating an intramolecular hydrogen bonding motif. The frontrunner of the series, analogue A, showed nanomolar activity against the chloroquine-sensitive NF54 and multi-drug-resistant K1 strains of Plasmodium falciparum (PfNF54 IC(50) = 0.079 μM; PfK1 IC(50) = 0.335 μM). Here, we describe a cell-based medicinal chemistry structure–activity relationship study using compound A as a basis. This effort led to the identification of novel antimalarial imidazopyridines with activities of <1 μM, favorable cytotoxicity profiles, and good physicochemical properties. Analogue 14 ( PfNF54 IC(50) = 0.08 μM; PfK1 IC(50) = 0.10 μM) was identified as the frontrunner of the series. Preliminary mode of action studies employing molecular docking, live-cell confocal microscopy, and a cellular heme fractionation assay revealed that 14 does not directly inhibit the conversion of heme to hemozoin, although it could be involved in other processes in the parasite’s digestive vacuole.