Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Here we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,600-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 cells, which is largely driven by the accommodation of the parasite proteasome for a d-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs. ### Competing Interest Statement The authors have declared no competing interest. * Leu : Leucine Phe : Phenylalanine EK : Epoxyketone t -butyl : tertiary-butyl c20S : human constitutive 20S Pf20S : P. falciparum 20S IP : intraperitoneal IV : intravenous PK : pharmacokinetics SI : selectivity index