NDLI: New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic α,α-difluoroketone hydrates

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New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic α,α-difluoroketone hydrates

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Introduction of methyl groups on vinylene segments of phenylene vinylene systems: synthesis and properties

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New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic α,α-difluoroketone hydrates

Content Provider	Royal Society of Chemistry (RSC)
Author	Hardegger, Leo A. Baitsch, Lukas Diederich, François Schweizer, W. Bernd Fäh, Christoph Meyer, Solange Bur, Daniel
Copyright Year	2009
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 α,α-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 α,α-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 IC50 value (concentration of an inhibitor at which 50% maximum initial velocity is observed) of 7 μM 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 α,α-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 α,α-difluorinated cyclohexanones are much higher than those for the corresponding cyclopentanones.
Starting Page	3947
Ending Page	3957
Page Count	11
File Format	HTM / HTML PDF
ISSN	14770520
Volume Number	7
Issue Number	19
Journal	Organic & Biomolecular Chemistry
DOI	10.1039/b908489d
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	X-ray crystallography Plasmodium Ammonium Hydrate Malaria Enzyme Ligand IC50 Alicyclic compound Enzyme inhibitor Plasmepsin
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Physical and Theoretical Chemistry

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Crystallization and preliminary X-ray analysis of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae.

Activity and inhibition of plasmepsin IV, a new aspartic proteinase from the malaria parasite, Plasmodium falciparum.

Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum

Prodomain processing of recombinant plasmepsin ii and iv, the aspartic proteases of plasmodium falciparum, is auto (2006).

Structure and inhibition of plasmepsin II , a hemoglobin-degrading enzyme from Plasmodiumfalciparum ( malaria / drug design / crystallography / aspartic protease / cathepsin D )

Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.

Parasite Killing in Plasmodium vivax Malaria by Nitric Oxide: Implication of Aspartic Protease Inhibition

Antiplasmodial activity of short peptide-based compounds

Selective inhibitors of plasmepsin II of Plasmodium falciparum on the basis of pepstatin

New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic α,α-difluoroketone hydrates

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Crystallization and preliminary X-ray analysis of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae.

Activity and inhibition of plasmepsin IV, a new aspartic proteinase from the malaria parasite, Plasmodium falciparum.

Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum

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Antiplasmodial activity of short peptide-based compounds

Selective inhibitors of plasmepsin II of Plasmodium falciparum on the basis of pepstatin

New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic α,α-difluoroketone hydrates