title: New inhibitors of the malaria aspartyl proteases plasmepsin I and II.
abstract: New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits K(i) values of 250 nM and 1.4 microM for Plm I and II, respectively.
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: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008288:Malaria / Q000188:drug therapy; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins
chemical_list: D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II