title: Improved 2,4-diarylthiazole-based antiprion agents: switching the sense of the amide group at C5 leads to an increase in potency.
abstract: Amide derivatives of 2,4-diarylthiazole-5-carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4-diphenyl-5-aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5-diaryl-1,2,4-thiadiazoles isolated as by-products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrP(C)) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrP(C).
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S7 3HF, UK. m.j.thompson@sheffield.ac.uk
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Louth
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Greenwood
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Sorrell
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Knight
authors.forename: Nathan B P
authors.initials: NB
authors.lastname: Adams
authors.forename: Beining
authors.initials: B
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000577:Amides; D011328:Prions; D013844:Thiazoles