Experimental and computational evaluation of new quinolinyl chalcones as potent antiplasmodial agents

1780-1793 In a search for new antiplasmodial agents, a series of thirty five diversely substituted chalcones derived from a quinoline-chalcone scaffold e.g. (E)-3-(2-chloroquinolin-3-yl)-1-(2-hydroxyphenyl) prop-2-en-1-one / (E)-(2-chloro-6-ethoxyquinolin-3-yl) (2-hydroxyphenyl) prop-2-en-1-one and (2Z)-3-(2-chloroquinolin-3-yl)-1-(2-hydroxyphenyl)-3-iodoprop-2-en-1-one are synthesized and studied. Compounds are prepared via Claisen–Schmidt condensations of 2-chloro-3-formyl quinoline / 2-chloro-6-ethoxy-3-formyl quinoline with appropriately substituted 2-hydroxy acetophenones. All compounds are assayed for their binding in the active sites of Plasmodium falciparum lactate dehydrogenase (pfLDH) enzyme. The quinoline chalcone derivatives showed negative binding energies promising potent pfLDH inhibitory activity. Compounds showing the highest negative binding scores have been studied for their in vitro antimalarial activity against cultured Plasmodium falciparum 3D7 strain. The compounds 2c and 2u have completely inhibited the maturation of parasites at MIC 10 µg/mL and above whereas 3b inhibited 95% maturation of parasites at MIC 50 µg/mL. Additional efforts are being directed towards elaborating these leads towards the discovery and development of new quinolinyl heterocycles as anti-malarial agents.