Plasmodium species are the causative agents of malaria, infecting 300-660 million people annually and killing 1-2 million. Malaria is undisputedly a disease of poverty and suffers from a lack of business-driven drug research, therefore requiring new initiatives to overcome this absence of market incentives. Low cost-of-goods for antimalarial drugs is a necessity for medical success. Increasing emergence of multiple drug-resistant parasites rapidly decreases the number of effective and cheap antimalarial agents and further aggravates the already devastating social and economic situations in many endemic areas. In the search for new drugable parasite targets, a family of aspartic proteinases (plasmepsins) has been identified in the digesting vacuole of P. falciparum. Whereas initial studies have identified only three plasmepsins a systematic search in the fully sequenced genome of P. falciparum has expanded the family to ten members. Subsequent sequence alignments and knockout studies revealed three aspartic proteinases (PMI, PMII, and PMIV) and the highly related histo-aspartic proteinase HAP (PMIII) located in the food vacuole. These four plasmepsins are mutually redundant and engaged in hemoglobin degradation-a process apparently vital for the parasite.
Recently, a new class of achiral, easily synthesizable, and highly potent inhibitors of PMII has been identified in our lab and a well resolved X-ray structure of a PMII-inhibitor 1 complex has been determined. Initial inhibitors were very selective against the human enzymes cathepsin D, E, and renin, however, they were also virtually inactive against the vacuolar PMII paralogs PMI and PMIV. Herein, structure supported design and synthesis of a new class of nonpeptidomimetic compounds is described. Compounds were obtained from a central 4-aminopiperidine with three substituents (A, B, C) (Figure a) yielding cheap, achiral, and highly potent inhibitors of all three vacuolar aspartic proteinases (PMI, II, and IV).