RESUMO
The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Química Computacional , Cisteína , Dissulfiram/metabolismo , Dissulfiram/farmacologia , Humanos , Simulação de Acoplamento Molecular , Papaína , Peptídeo Hidrolases , Inibidores de Proteases/química , SulfóxidosRESUMO
BACKGROUND/OBJECTIVES: 4-(Arylchalcogenyl)-1H-pyrazoles containing selenium or sulfur (0.001-50 mg/kg) were investigated regarding the intragastric route effect (ig) administration on nociception in mice. In this study, nociception and inflammation were induced by chemical agents such as formalin (0.92%), sodium L-glutamate 1-hydrate (20 µmol), croton oil (2.5%), acetic acid (1.6%) and thermic model with a hot plate test. RESULTS: Compounds 1a-c had the ability to reduce licking time in both phases (neurogenic and inflammatory) of the formalin test and glutamate. Only compounds 1a and 1b had the ability to reduce the number of abdominal writhes caused by acetic acid. The same was observed with the positive control celecoxib. To evaluate the possible anti-inflammatory activity of compounds 1a-c, the induction of paw edema by formalin and ear edema by croton oil was performed. For the inflammation induced by formalin, significant effects were observed from the dose of 0.1 mg/kg (1a-b) and 10 mg/kg (1c). In the ear edema test, it can be observed that only compound 1a had a significant effect. In the hotplate test, all the compounds had the ability to reduce the latency time. CONCLUSION: The results demonstrated that acute antinociceptive and anti-inflammatory effects of 4-(arylchalcogenyl)-1H-pyrazoles 1a is better than compared with the compound 1b and 1c in mice. This resulted in these molecules attracting the interest of researchers to perform future studies to develop new drugs to treat pain and inflammatory clinical conditions.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Pirazóis/farmacologia , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Celecoxib/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/química , Selênio/química , Enxofre/químicaRESUMO
The mechanisms that lead to the onset of organoselenium intoxication are still poorly understood. Therefore, in the present study, we investigated the effect of acute administration of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress and on the activity of creatine kinase (CK) in different brain areas and on the behaviour in the open field test of 90-day-old male rats. Animals (n = 10/group) were treated intraperitoneally with a single dose of the organoselenium (125, 250 or 500 µg kg(-1) ), and after 1 h of the drug administration, they were exposed to the open field test, and behaviour parameters were recorded. Immediately after they were euthanized, cerebral cortex, hippocampus and cerebellum were dissected for measurement of thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD) and CK activity. Our results showed that the dose of 500 µg kg(-1) of the organoselenium increased the locomotion and rearing behaviours in the open field test. Moreover, the organochalcogen enhanced TBARS in the cerebral cortex and cerebellum and increased the oxidation of proteins (carbonyl) only in the cerebral cortex. Sulfhydryl content was reduced in all brain areas, CAT activity enhanced in the hippocampus and reduced in the cerebellum and SOD activity increased in all brain structures. The organoselenium also inhibited CK activity in the cerebral cortex. Therefore, changes in motor behaviour, redox state and energy homeostasis in rats treated acutely with organoselenium support the hypotheses that the brain is a potential target for the organochalcogen action. Ltd.
Assuntos
Encéfalo/metabolismo , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/enzimologia , Catalase/metabolismo , Creatina Quinase/metabolismo , Masculino , Compostos Organosselênicos/química , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
In this study we have examined the in vivo toxic effects of various organochalcogens on hepatic, renal, glycemic and lipid profile. Diorganotellurium dichloride phosphonate (C1) at all tested doses did not modify serum alanine aminotransferase (ALT) activity in mice. While, 2-butyltellurium furan (C2) and dinaphthalene ditelluride (C3) at a dose of 0.75 and 0.125 mmol/kg caused an increase in aspartate aminotransferase (AST) and ALT activities. Our data showed that C1 caused an increase in urea content at different doses while treatment with C2 and C3 did not modify urea content. Treatment with C2 caused a significant alteration in serum glucose and fructosamine levels which explains the possible toxicity of these compounds. No significant changes were observed for cholesterol and triglycerides levels. These results suggest that organochalcogen compounds presented liver and renal toxicity and also altered glycemic profile which may leads to various clinical complications.