Search for substrate-based inhibitors fitting the S₂′ space of malarial aspartic protease plasmepsin II

Plasmepsin (Plm) has been identified as an important target for the development of new antimalarial drugs, since its inhibition leads to the starvation of Plasmodium falciparum. A series of substrate-based dipeptide-type Plm II inhibitors containing the hydroxymethylcarbonyl isostere as a transition-state mimic were synthesized. The general design principle was provision of a conformationally restrained hydroxyl group (corresponding to the set residue at the P₂′ position in native substrates) and a bulky unit to fit the S₂′ pocket.