Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model

Abstract

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue <b>1</b> with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue <b>23</b> (<i>Pf</i>NF54 IC₅₀ = 0.012 μM; <i>Pf</i>K1 IC₅₀ = 0.040 μM) displaying high microsomal metabolic stability (HLM CL_int < 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 <i>in vivo</i> efficacy in <i>Plasmodium berghei</i>-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 <b>23</b> 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.