Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC50 = 0.012 μM; PfK1 IC50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CLint < 11.6 μL·min-1·mg-1) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg·kg-1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.