title: Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II.
abstract: With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 microM (K(i) for Plm II=5.4 microM).
authors.affiliation: Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Dahlgren
authors.forename: Ingemar
authors.initials: I
authors.lastname: Kvarnström
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D019151:Peptide Library; D010961:Plasmodium / Q000201:enzymology*; D015800:Protozoan Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000962:Antimalarials; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D019151:Peptide Library; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II; C013165:statine