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Our best compound has more than 2,000\u2010fold greater selectivity for erythrocytic\u2010stage <jats:italic>P.\u2005falciparum<\/jats:italic> over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D\u2010amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from <jats:italic>P.\u2005falciparum<\/jats:italic> cell extracts and determined that the best compound is 171\u2010fold more potent at inhibiting the \u03b25 subunit of <jats:italic>P.\u2005falciparum<\/jats:italic> proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a <jats:italic>P. berghei<\/jats:italic> mouse infection model and prolong survival of animals by an average of 6\u2005days. 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