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This article discusses the development of a new series of flexible biphenyl compounds that show improved antiparasitic activity compared to rigid inhibitors. The compounds utilize a flexible linker and strong hydrophobic interactions for binding, leading to enhanced efficacy against malaria. The best compound in the series displays a 2 nM antiplasmodial IC50 and shows suitable drug-like properties. This research highlights the importance of compound flexibility in designing effective antimalarial drugs and opens up new avenues for drug development in this area.
As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with high safety profile and extended efficacy. In a previous study, a rigid biphenyl PfDHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC50 and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design.
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