title: Potent inhibitors of malarial aspartic proteases, the plasmepsins, by hydroformylation of substituted 7-azanorbornenes.
abstract: The increasing prevalence of multidrug-resistant strains of the malarial parasite Plasmodium falciparum requires the urgent development of new therapeutic agents with novel modes of action. The vacuolar malarial aspartic proteases plasmepsin (PM) I, II, and IV are involved in hemoglobin degradation and play a central role in the growth and maturation of the parasite in the human host. We report the structure-based design, synthesis, and in vitro evaluation of a new generation of PM inhibitors featuring a highly decorated 7-azabicyclo[2.2.1]heptane core. While this protonated central core addresses the catalytic Asp dyad, three substituents bind to the flap, the S1/S3, and the S1' pockets of the enzymes. A hydroformylation reaction is the key synthetic step for the introduction of the new vector reaching into the S1' pocket. The configuration of the racemic ligands was confirmed by extensive NMR and X-ray crystallographic analysis. In vitro biological assays revealed high potency of the new inhibitors against the three plasmepsins (IC(50)  values down to 6 nM) and good selectivity towards the closely related human cathepsins D and E. The occupancy of the S1' pocket makes an essential contribution to the gain in binding affinity and selectivity, which is particularly large in the case of the PM IV enzyme. Designing non-peptidic ligands for PM II is a valid route to generate compounds that inhibit the entire family of vacuolar plasmepsins.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zurich, Hönggerberg HCI, 8093 Zurich, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Aureggi
authors.forename: Veronika
authors.initials: V
authors.lastname: Ehmke
authors.forename: Joerg
authors.initials: J
authors.lastname: Wieland
authors.forename: W Bernd
authors.initials: WB
authors.lastname: Schweizer
authors.forename: Bruno
authors.initials: B
authors.lastname: Bernet
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Céline
authors.initials: C
authors.lastname: Freymond
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Bernhard
authors.initials: B
authors.lastname: Breit
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005557:Formaldehyde / Q000737:chemistry*; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D006536:Heptanes; D011480:Protease Inhibitors; D005557:Formaldehyde; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin