title: Library synthesis and screening: 2,4-diphenylthiazoles and 2,4-diphenyloxazoles as potential novel prion disease therapeutics.
abstract: Transmissible spongiform encephalopathies (TSEs) are a family of invariably fatal neurodegenerative disorders for which no effective therapeutics are currently available. In this paper, we report on the synthesis and screening of a small library of 2,4-diphenylthiazol-5-ylamine and 2,4-diphenyloxazol-5-ylamine derivatives as potential novel prion disease therapeutics. Various synthetic strategies were investigated, including a novel phosgene-mediated cyclization of 2-N-benzoylphenylglycinonitrile, and a total of 45 compounds were synthesized. Library members were tested for both binding to prion protein (PrPC) using the surface plasmon resonance technique and for inhibition of PrPSc formation in persistently infected SMB cells. Of the compounds prepared, 15 were found to bind to human PrPC and six showed inhibition of PrPSc formation, displaying EC50s between 1.5 and 20 microM.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK.
authors.forename: William
authors.initials: W
authors.lastname: Heal
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Roger
authors.initials: R
authors.lastname: Mutter
authors.forename: Hannah
authors.initials: H
authors.lastname: Cope
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Louth
authors.forename: Beining
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018621:PrPC Proteins / Q000737:chemistry; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017096:Prion Diseases / Q000188:drug therapy*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010080:Oxazoles; D018621:PrPC Proteins; D018620:PrPSc Proteins; D013844:Thiazoles