Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.
The increasing resistance of the malarial parasite to antimalarial drugs is a major contributor to the reemergence of the disease and increases the need for new drug targets. The two aspartic proteases, plasmepsins I and II, from Plasmodium falciparum have recently emerged as potential targets. In an effort to inhibit these hemoglobinases, a series of inhibitors encompassing a basic hydroxyethylamine transition state isostere as a central fragment were prepared. The synthesized compounds were varied in the P1' position and exhibited biological activities in the range of 31 to >2000 nM. To try to rationalize the results, molecular docking and 3D-QSAR analysis were used.
Muthas
Daniel
D
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Nöteberg
Daniel
D
Sabnis
Yogesh A
YA
Hamelink
Elizabeth
E
Vrang
Lotta
L
Samuelsson
Bertil
B
Karlén
Anders
A
Hallberg
Anders
A
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D008954:Models, Biological; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins; D021281:Quantitative Structure-Activity Relationship
D000962:Antimalarials; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II