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.
After a century since the first antimonial-based drugs were introduced to treat the disease, anti-schistosomiasis drug development is again at a bottleneck with only one drug, praziquantel, available for treatment purposes.
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.
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