Flavones as isosteres of 4(1H)-quinolones: Discovery of ligand efficient and dual stage antimalarial lead compounds

• First report of synthetic flavones with dual antiplasmodial activity.
• Report of flavones as isosteres of 4(1H)-quinolones.
• Modular synthesis of flavones allows fast exploration of chemical space.
• Report of ligand efficient flavones as leads for medicinal chemistry optimization.

Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of P. falciparum W2 strain, and the liver stage of the rodent parasite Plasmodium berghei. Ligand efficient leads were identified as dual stage antimalarials, suggesting that scaffold optimization may afford potent antiplasmodial compounds.

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