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. A novel class of benzimidazole acrylonitriles was biologically evaluated against Plasmodium falciparum and for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain‐2 enzyme binding. The compounds displayed dual inhibition (falcipain‐2 and hemozoin formation). The most active compound, 2‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐(3‐methoxyphenyl)acrylonitrile R‐01, had antimalarial activity at 0.69 µM.