title: Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity.
abstract: The hemoglobin-degrading aspartic proteases plasmepsin I (Plm I) and plasmepsin II (Plm II) of the malaria parasite Plasmodium falciparum have lately emerged as putative drug targets. A series of C(2)-symmetric compounds encompassing the 1,2-dihydroxyethylene scaffold and a variety of elongated P1/P1' side chains were synthesized via microwave-assisted palladium-catalyzed coupling reactions. Binding affinity calculations with the linear interaction energy method and molecular dynamics simulations reproduced the experimental binding data obtained in a Plm II assay with very good accuracy. Bioactive conformations of the elongated P1/P1' chains were predicted and agreed essentially with a recent X-ray structure. The compounds exhibited picomolar to nanomolar inhibition constants for the plasmepsins and no measurable affinity to the human enzyme cathepsin D. Some of the compounds also demonstrated significant inhibition of parasite growth in cell culture. To the best of our knowledge, these plasmepsin inhibitors represent the most selective reported to date and constitute promising lead compounds for further optimization.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Ersmark
authors.forename: Isabella
authors.initials: I
authors.lastname: Feierberg
authors.forename: Sinisa
authors.initials: S
authors.lastname: Bjelic
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Fiona
authors.initials: F
authors.lastname: Hackett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.forename: Johan
authors.initials: J
authors.lastname: Hultén
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003198:Computer Simulation; D004912:Erythrocytes / Q000469:parasitology; D005030:Ethylenes / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000577:Amides; D005030:Ethylenes; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D