title: New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic alpha,alpha-difluoroketone hydrates.
abstract: The development of new therapeutic agents against malaria has become urgent during the past few decades, due to an increased prevalence of drug-resistant strains of malaria-causing Plasmodium parasites. Possible targets are the hemoglobin-degrading aspartic proteases, the plasmepsins. While acyclic alpha,alpha-difluoroketone hydrates have been introduced into peptidomimetics to bind to the catalytic Asp dyad of aspartic proteases, alicyclic derivatives were unknown. This paper describes a versatile synthesis of hydrated alicyclic alpha,alpha-difluoro-cyclopentanones and -cyclohexanones, decorated with appropriate substituents to fill the S1/S3 and the "flap-open" pocket at the enzyme active sites. Their biological activity was tested against plasmepsin II and IV, revealing an IC(50) value (concentration of an inhibitor at which 50% maximum initial velocity is observed) of 7 microM for the best ligand. Reference inhibitors with a protonated secondary ammonium centre to address the catalytic dyad showed similar binding affinities. The X-ray crystal structure of a cyclic alpha,alpha-difluoroketone hydrate revealed the ability of these novel building blocks to participate in H-bonding networks. The hydration of difluoroketones was also investigated in solution. An exemplary study showed that the equilibrium constants for the hydration of alpha,alpha-difluorinated cyclohexanones are much higher than those for the corresponding cyclopentanones.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, CH-8093, Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fäh
authors.forename: Leo A
authors.initials: LA
authors.lastname: Hardegger
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.forename: W Bernd
authors.initials: WB
authors.lastname: Schweizer
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
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; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008288:Malaria / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D000962:Antimalarials; D007659:Ketones; D011480:Protease Inhibitors; D014867:Water; D005461:Fluorine; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin