Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment

Membrane-bound
pyrophosphatases (mPPases) regulate energy homeostasis
in pathogenic protozoan parasites and lack human homologues, which
makes them promising targets in e.g. malaria. Yet
only few nonphosphorus inhibitors have been reported so far. Here,
we explore an isoxazole fragment hit, leading to the discovery of
small mPPase inhibitors with 6–10 μM IC50 values
in the Thermotoga maritima test system. Promisingly,
the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.