Improved 2,4-diarylthiazole-based antiprion agents: switching the sense of the amide group at C5 leads to an increase in potency.
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).
Thompson
Mark J
MJ
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S7 3HF, UK. m.j.thompson@sheffield.ac.uk
Louth
Jennifer C
JC
Greenwood
Gemma K
GK
Sorrell
Fiona J
FJ
Knight
Sandra G
SG
Adams
Nathan B P
NB
Chen
Beining
B
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
D000577:Amides; D011328:Prions; D013844:Thiazoles