期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 49, 期 17, 页码 5300-5308出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm0602763
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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.
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