Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes.
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).
Nöteberg
Daniel
D
Division of Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE - 751 23 Uppsala, Sweden.
Hamelink
Elizabeth
E
Hultén
Johan
J
Wahlgren
Mats
M
Vrang
Lotta
L
Samuelsson
Bertil
B
Hallberg
Anders
A
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
D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II