title: Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Muthas
authors.forename: Daniel
authors.initials: D
authors.lastname: Nöteberg
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sabnis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
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: Karlén
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: 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
chemical_list: D000962:Antimalarials; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II