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.