An altered form of the cellular
prion protein, the PrPScor PrPRes, 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 (PrPRes) 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.