Improved 2,4-Diarylthiazole-Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

• Published in: ChemMedChem 2010-09, Vol.5 (9), p.1476-1488
• Main Authors: Thompson, Mark J., Louth, Jennifer C., Greenwood, Gemma K., Sorrell, Fiona J., Knight, Sandra G., Adams, Nathan B. P., Chen, Beining
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Animals; Cell Line; drug discovery; Humans; medicinal chemistry; Mice; Microsomes, Liver - metabolism; prion disease; Prions - antagonists & inhibitors; Prions - metabolism; Structure-Activity Relationship; structure-activity relationships; thiazoles; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - toxicity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000217

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 (PrPC) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrPC. A number of 2,4‐diarylthiazole‐5‐carboxamides were identified as potent antiprion agents in a scrapie‐infected cell line. This class of compounds outperformed the previously reported amide derivatives of 2,4‐diphenyl‐5‐aminothiazole in terms of antiprion activity. Furthermore, 3,5‐diaryl‐1,2,4‐thiadiazoles isolated as side‐products during library synthesis serendipitously provided additional compounds with useful biological activity.