title: Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes.
abstract: A series of protease inhibitors targeted at the malarial enzymes plasmepsin I and II, and encompassing a basic hydroxyethylamine transition state isostere scaffold, was prepared. The substituents in the P1' position were varied and the biological activities expressed in K(i)-values ranged from 60 to >2000 nM. A more than 4-fold selectivity for either of the plasmepsins could be achieved. All of the active compounds exhibited high preference for the plasmepsins over cathepsin D, the most closely related human protease. A few active compounds were shown to inhibit parasite growth in cultured infected human erythrocytes. An ED(50) value as low as 1.6 microM was observed for one of the inhibitors despite K(i) values of 115 nM (Plm I) and 121 nM (Plm II).
authors.affiliation: Division of Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE - 751 23 Uppsala, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nöteberg
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Johan
authors.initials: J
authors.lastname: Hultén
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; 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