Synthesis and antimalarial activity of quinoline-substituted furanone derivatives and their identification as selective falcipain-2 inhibitors

3-[(2-Chloroquinolin-3-yl) methylene]-5-phenylfuran-2(3H)-one derivatives (6a-j and 7a-j) have been synthesized and evaluated for their antimalarial activity. Three compounds 7d, 7f, and 7g showed excellent activity (0.50-0.72 A mu g/mL). In addition, six compounds were active in range below 5 A mu g/mL. A preliminary structure-activity relationship analysis of the series suggested that electropositive character is beneficial for antimalarial activity. Falcipain-2 was identified as potential target for the compounds by in silico studies. The docking studies of synthesized compounds on falcipain-2 revealed vital interactions and their binding conformation. Compound 7d and 7f could be used as lead to develop selective falcipain-2 inhibitors as they showed good inhibition of the enzyme in enzyme assay studies.