Malaria, a life-threatening disease caused by parasites of the genus Plasmodium, affects 500 million people annually, of which more than one million die. [1] The emergence of multi-drugresistant strains of Plasmodium falciparum, the parasite that causes the deadliest form of malaria, exacerbates the situation and necessitates new medicines with novel modes of action. [2] Plasmepsin II (PII; EC 3.4.23.39), [3] a parasitic aspartic protease involved in the hemoglobin degradation process that takes place in an acidic vacuole, has been identified as a potential target for antimalarial therapy. Several groups reported PII inhibitors that mimic the natural substrate and display up to single-digit nanomolar activity. [4] Inhibition of PII is expected to block the life cycle of the parasite. [5] Here we report the synthesis and in vitro evaluation of a new class of nonpeptidic PII inhibitors developed with the help of structure-based de novo design that show up to single-digit micromolar inhibitory activities. [6±8] A major conformational change around the active site of the human aspartic protease renin (EC 3.4.23.15) upon complexation of 3,4-disubstituted piperidines has been observed, which unveils unexpected flexibility of the enzyme. [9] The flap that lies over the catalytic dyad, and a tryptophan side chain of the core domain, move and thereby unlock a new hydrophobic pocket (flap pocket). The high sequence homology between renin and PII prompted us to hypothesize that an induced-fit adaptation such as that of the active site of renin might also be operative