NR AVFY
AU Klingenstein,R.; Melnyk,P.; Leliveld,S.R.; Ryckebusch,A.; Korth,C.
TI Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects
QU Journal of Medicinal Chemistry 2006 Aug 24; 49(17): 5300-8
PT journal article
AB Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrPsc, a pathogenic misfolded isoform of the normal cellular prion protein (PrPc). 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.
MH Animals; Antimalarials/chemical synthesis/chemistry/*pharmacology; Cell Line, Tumor; Chloroquine/analogs & derivatives/chemical synthesis/pharmacology; Drug Evaluation, Preclinical; Mice; Molecular Structure; Prions/*antagonists & inhibitors; Quinolines/chemical synthesis/chemistry/*pharmacology; Research Support, Non-U.S. Gov't; Stereoisomerism; Structure-Activity Relationship
AD Institute for Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
SP englisch
PO USA