Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition.

Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 μM), R-04 (1.60 μM), and R-08 (1.61 μM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.