title: Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects.
abstract: Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.
authors.affiliation: Institute for Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Klingenstein
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
authors.forename: S Rutger
authors.initials: SR
authors.lastname: Leliveld
authors.forename: Adina
authors.initials: A
authors.lastname: Ryckebusch
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D051379:Mice; D015394:Molecular Structure; D011328:Prions / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011328:Prions; D011804:Quinolines; D002738:Chloroquine