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).

Discovery of a Novel, Monocationic, Small-Molecule Inhibitor of Scrapie Prion Accumulation in Cultured Sheep Microglia and Rov Cells

“…It is, however, lower than others: dextran sulfate 500 (>250) and Congo red (>17) [65]. Furthermore, the SI is similar to other less commonly studied compound classes with potentially significant anti-prion activity such as diarylthiazoles (SI: 3.3) [66]. Our curcumin data indicate that cell death does not necessarily dictate a decrease in PrP Sc levels and that nonspecific effects associated with cell death do not cause the anti-PrP Sc effects in this study, i.e., while the anti-prion mechanism of DB772 may or may not be closely related to its toxicity, there is no evidence that cell death is the mechanism of the inhibition.…”

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

“…[14] In the light of these results, direct aminolysis of ester 10 was investigated in a solvent-free procedure mediated by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). [15] Although this methodology has proven successful in other contexts in our laboratory, [16] none of the desired amide product 5 b was detected upon reaction of 10 with p-anisidine under these conditions. As an alternative strategy, reaction of indole with monobenzyl malonate was carried out, successfully resulting in isolation of benzyl ester 11.…”

“…[16,21] Experiments were carried out using a Biacore 3000 instrument equipped with a CM5 sensor chip, containing a CM-dextran surface. Prior to screening, PrP C was immobilised on the chip surface according to the following protocol: A 1:1 mixture of 100 mm N-hydroxysuccinimide and 400 mm EDC was passed over the sensor chip for 7 min at a flow rate of 5 mL min…”

Prion Disease: Chemotherapeutic Strategies

“…This group of compounds, and its derivatives, has recently been found to have anti-prion effects in cell culture [114,115], and subsequent modifications have led to the study of (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)thiazol-2-yl]-amine, which has high efficacy in cells and also can cross the blood-brain barrier [116]. In vivo studies are not yet available.…”