| Summary: | Malaria parasites continue to pose a concern. Drug resistance underlines the need for new structural cores that, when combined with existing antimalarial frameworks, can partially re-sensitize drug-resistant parasites to available antimalarial drugs, such as chloroquine (CQ). Herein, we used “covalent biotherapy” to design and synthesize a series of aminoquinoline-oxindoles. The most promising hybrid exhibited an IC50 value of 30.9 nM against the drug-resistant W2 strain of P. falciparum, and was seven-fold more active than CQ. To decipher the mode of action, UV–Vis spectral and molecular modelling studies were performed, demonstrating that the hybrid exerts antiplasmodial effects via hemozoin (aminoquinoline) and PfCRT inhibition (oxindole), demonstrating its dual-functionality. To the best of our knowledge, this is the first report of an oxindole core acting as a potential PfCRT inhibitor, which could be a key component in the development of CQ-based chemosensitizers in the near future.
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