New inhibitors of the malaria aspartyl proteases plasmepsin I and II.
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.
Dahlgren
Anders
A
Department of Chemistry, Linköping University, S-581 83, Linköping, Sweden.
Kvarnström
Ingemar
I
Vrang
Lotta
L
Hamelink
Elizabeth
E
Hallberg
Anders
A
Rosenquist
Asa
A
Samuelsson
Bertil
B
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
D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II