Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles
Document title: Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles
Journal: Anais da Academia Brasileira de Ciencias
Database: PERIÓDICA
System number: 000391330
ISSN: 0001-3765
Authors: 1
1
1
1
1
1
2
2
2
2
1
Institutions: 1Universidade Federal do Rio de Janeiro, Faculdade de Farmacia, Rio de Janeiro. Brasil
2Universidade Federal de Santa Catarina, Departamento de Quimica, Florianopolis, Santa Catarina. Brasil
Year:
Season: Ago
Volumen: 87
Number: 2
Pages: 1421-1434
Country: Brasil
Language: Inglés
Document type: Artículo
Approach: Experimental, aplicado
English abstract An altered form of the cellular prion protein, the PrPSc or 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
Portuguese abstract Uma forma alterada da proteína prion celular, a PrPSc ou PrPRes, está envolvida na ocorrência das encefalopatias espongiformes transmissíveis. Nós sintetizamos e caracterizamos previamente compostos aromáticos que inibem o acúmulo da proteína prion resistente a proteases (PrPRes) em células infectadas com prion scrapie. Estes compostos pertencem a diferentes classes químicas, incluindo acilhidrazonas, chalconas e oxadiazóis. Alguns dos compostos ativos não apresentaram toxicidade para células de neuroblastoma em cultura e parecem apresentar propriedades de fármacos, uma vez que todos obedecem aos 5 quesitos da regra de Lipinski e apresentam perfil farmacocinético desejável, como predito in silico. Antes de avaliar a eficácia in vivodos compostos aromáticos em camundongos infectados com prion scrapie, é necessário estimar sua segurança em camundongos saudáveis. Neste trabalho nós utilizamos camundongos Suíços para avaliar o perfil de toxicidade aguda dos seis compostos mais promissores, as 2,4,5-trimetoxichalconas (J1, J8, J20 e J35) e os 1,3,4-oxadiazóis (Y13 e Y17). Administração oral em dose única (300 mg/kg) de J1, J8, J20, J35, Y13 e Y17 ou administração repetida via intraperitoneal (10 mg/kg, 3 vezes por semana, por 4 semanas) de J1, J8 e J35, não geraram toxicidade nos camundongos. Nós acreditamos fortemente que as trimetoxichalconas e os oxadiazóis investigados são compostos interessantes para serem futuramente avaliados in vivo contra as doenças causadas por prions
Disciplines: Medicina
Keyword: Farmacología,
Neurología,
Priones,
Encefalopatía espongiforme,
Trimetoxichalconas,
Oxadiazoles,
Toxicidad,
Farmacocinética
Keyword: Medicine,
Neurology,
Pharmacology,
Prions,
Spongiform encephalopathy,
Trimethoxychalcones,
Oxadiazoles,
Toxicity,
Pharmacokinetics
Full text: Texto completo (Ver HTML)