title: New potent C2-symmetric malaria plasmepsin I and II inhibitors.
abstract: A series of malaria plasmepsin (Plm) I and II inhibitors containing a C(2)-symmetric core structure have been synthesised and tested for protease inhibition activity. These compounds can be prepared using a straightforward synthesis involving a phenol nucleophilic ring opening of a diepoxide. Exemplar compounds synthesised exhibited remarkable inhibitory activity against both Plm I and II, notably 15c with K(i) values of 2.7nM and 0.25nM respectively, as well as showing >100-fold selectivity against Cathepsin D.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Floor 6, Stockholm University, S-106 91, Stockholm, Sweden. bertil.samuelsson@medivir.se
authors.forename: Karin
authors.initials: K
authors.lastname: Oscarsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000215:Acylation; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002402:Cathepsin D / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D