RESUMO
The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 µM and 8 µM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.
Assuntos
Antivirais/química , Quercetina/química , SARS-CoV-2/metabolismo , Selênio/química , Proteínas da Matriz Viral/antagonistas & inibidores , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Chlorocebus aethiops , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Quercetina/metabolismo , Quercetina/farmacologia , SARS-CoV-2/isolamento & purificação , Selênio/metabolismo , Células Vero , Proteínas da Matriz Viral/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Glaucopine A (1) and B (2), two new cyathane diterpenes, have been isolated from the mushroom Sarcodon glaucopus: their structures have been determined on the basis of spectral data. Their topical anti-inflammatory activity was evaluated using the Croton oil ear test in mice: compounds 1 and 2 (1 micromol/cm2) provoked edema reduction (62 % and 55 %, respectively) similar to that induced by the reference non-steroidal anti-inflammatory drug, indomethacin (0.3 micromol/cm2, 61 % edema reduction).
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Basidiomycota , Edema/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Óleo de Cróton , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Edema/induzido quimicamente , Frutas , Masculino , Camundongos , Camundongos Endogâmicos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêuticoRESUMO
Three sesquiterpene lactones were isolated from Lourteigia ballotaefolia (H. B. K.). 9beta-hydroxy-atripliciolide-8- O-tiglate ( 1) was isolated for the first time from this plant and was previously reported in Conocliniopsis prasiifolia (DC) K. et R., 9beta-hydroxy-atripliciolide-8- O-(5'-acetoxytiglate) ( 2) had been already reported in this species. The minor component, 9beta-(tigloyloxy)-atripliciolide, is a new compound. The anti-inflammatory activity of compounds 1 and 2 was evaluated using the croton oil ear test in mice.