In vitro efficacy of 2,N-bisarylated 2-ethoxyacetamides against Plasmodium falciparum

Investigation of a series of 2,N-bisarylated 2-ethoxyacetamides resulted in the identification of four inhibitors 5, 20, 24, 29 with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains. These compounds are analogs of structurally-related 1,3-bisaryl-2-propen-1-ones (chalcones), the latter showing efficacy in vitro but not in a malaria-infected mouse. The 2,N-bisarylated 2-ethoxyacetamides (e.g., 2, 5, 20) were shown to possess significantly greater stability in the presence of metabolizing enzymes than the corresponding 1,3-bisaryl-2-propen-1-ones (e.g., 1, 3, 18).

Graphical abstractFour inhibitors with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains were identified, including compound 20. They possess greater stability in the presence of metabolizing enzymes than do the corresponding 1,3-bisaryl-2-propen-1-ones, of which they are analogs.Figure optionsDownload full-size imageDownload as PowerPoint slide