Enhancing the Potency of the Antimalarial Agent, WEHI‐601, Through Stereoselective Fluorination

WEHI-601 is a statine-containing peptidomimetic that inhibits the malarial aspartyl protease, plasmepsin V. In this work, stereoselective fluorination is investigated as a strategy for enhancing the potency of WEHI-601 through conformational bias. Consistent with prediction, a fluorostatine-containing analogue of WEHI-601 is found to deliver stronger antimalarial activity than the lead compound, attributable to conformational preorganisation of the FCCO segment within the peptidomimetic backbone. However, the magnitude of the improvement is small, and this is discussed with reference to the hydrogen bonding capability of the vicinal fluoro-alcohol motif.