Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

Abstract

An altered form of the cellular prion protein, the PrP Sc or PrP Res, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrP Res ) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

Toxicity Study of 1-(2, 5-Dihidroxyphenil)-3-Pyridine-2-Il-Propenone In Adult Female Mice

“…The six trimethoxychalcones compounds tested did not show any significant toxicity in all organs/glands of experimental animals (Figueiredo et al, 2015). In contrast, this study showed toxicity effect of DPP on the liver and kidneys (Figure 5 and 6).…”

A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location

“…In a previous study, we analyzed a panel consisting of over 200 aromatic compounds and found four chalcones (compounds J1, J8, J20, and J35) and two oxadiazoles (compounds Y13 and Y17) able to decrease PrP Res levels by at least 50% in RML strain scrapie-infected N2a (ScN2a-RML) cells with 50% effective concentrations up to 10 M. Additionally, these compounds were devoid of toxicity for ScN2a cells and were predicted to have an adequate drug-like profile (23). The acute toxicity of these substances was evaluated in vivo, and we found that single oral administration (300 mg/kg of body weight) or repeated intraperitoneal administration (10 mg/kg 3 times a week for 4 weeks) did not cause toxic effects in mice (25). Based on these findings, in the study described here we analyzed by the RT-QuIC assay the efficacies of four of these compounds (compounds J1, J8, J20, and Y17, the structures of which are shown in Fig.…”

“…This construction lacks the N-terminal region, which comprises a critical binding site for PrP Sc and is therefore crucial for prion propagation. Mice expressing PrP C with a deletion in this region (a deletion from residues 23 to 31 [Δ [23][24][25][26][27][28][29][30][31] ]) exhibit resistance to prion infection, as evidenced by elongated incubation times and delayed accumulation of PrP Sc (45). PrP interaction with ligands putatively associated with its physiological function can also be mediated by this region (reviewed in references 17 and 46).…”

“…It is worth mentioning that one of the main reasons for the failure of various antiprion compounds as drugs is in vivo toxicity. In this sense, the selected compounds, which were previously tested in healthy mice (25), did not elicit acute toxicity, thus encouraging us to further investigate their mechanisms of action. Since two of the most common targets of antiprion drugs are PrP C and PrP Sc , we performed RT-QuIC reactions to check this possibility.…”

“…Using in silico approaches, these molecules were predicted to be sufficiently brain permeant, satisfactorily bioavailable after oral administration, and capable of binding to the same hydrophobic pocket of PrP C (23). Moreover, none of these compounds elicited acute toxicity in Swiss mice (25). Hence, the aromatic compounds J1, J8, J20, J35, Y13, and Y17 have been shown to be promising candidates for prion disease therapy.…”