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

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 IC50 = 0.079 µM; PfK1 IC50 = 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 IC50 = 0.08 µM; PfK1 IC50 = 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.

Incorporation of an intramolecular hydrogen bonding motif in the side chain of antimalarial benzimidazoles.

Analogues of a novel class of benzimidazoles with an intramolecular hydrogen bonding motif have been synthesized and evaluated in vitro for their antiplasmodium activity against chloroquine-sensitive (NF54) and multi-drug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. Compounds were also screened for their cytotoxicity towards a mammalian Chinese hamster ovarian (CHO) cell line. Most of the compounds exhibited good antiplasmodium activity (PfNF54 IC50 <1 µM) and were relatively noncytotoxic. Moreover, towards establishing the possible mode of action of these molecules, inhibition of beta-hematin formation was investigated and two compounds were found to be inhibitors. Single crystal X-ray data confirmed the existence of an intramolecular hydrogen bond.