Novel flexible biphenyl <i>Pf</i>DHFR inhibitors with improved antimalarial activity.

ABSTRACT: As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a 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 antiplas

SUBMITTER: Decharuangsilp S 

PROVIDER: S-EPMC11253869 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature