Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity andEfficacy in aMouse Malaria Infection Model.

Abstract

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analoguewith an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue(NF54 IC= 0.012 &#x3bc;M;K1 IC= 0.040 &#x3bc;M) displaying high microsomal metabolic stability (HLM CL< 11.6 &#x3bc;L&#xb7;min&#xb7;mg) 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 demonstratesefficacy in-infected mice at 4 &#xd7; 50 mg&#xb7;kgoral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed thatcould be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.