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Abstract
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.
Highlights
Flavonoids are valuable natural polyphenolic compounds endowed with a variety of biological properties [1] and are considered privileged scaffolds for rational drug design.This group of compounds has been extensively studied, primarily because of their pronounced antioxidant activity, which can proceed by several functioning mechanisms [1,2,3,4,5].Glutathione peroxidases (GPx) are a family of phylogenetically related redox enzymes developed by living systems as protection against reactive oxygen species
We reported a new metal-free protocol for the synthesis of a small library of selenoquercetin analogues
The most significant derivatives are endowed with a low micromolar potency which is better than that shown by quercetin, highlighting that the seleno-functionalization as well as the presence of the catechol unity improves the main protease (Mpro) inhibitory activity
Summary
Flavonoids are valuable natural polyphenolic compounds endowed with a variety of biological properties [1] and are considered privileged scaffolds for rational drug design.This group of compounds has been extensively studied, primarily because of their pronounced antioxidant activity, which can proceed by several functioning mechanisms [1,2,3,4,5].Glutathione peroxidases (GPx) are a family of phylogenetically related redox enzymes developed by living systems as protection against reactive oxygen species. Flavonoids are valuable natural polyphenolic compounds endowed with a variety of biological properties [1] and are considered privileged scaffolds for rational drug design. This group of compounds has been extensively studied, primarily because of their pronounced antioxidant activity, which can proceed by several functioning mechanisms [1,2,3,4,5]. Most of them are characterized by the presence of a selenocysteine in which the selenium atom is the actual catalyst for the glutathione-mediated reduction of peroxides [6], accounting for the essential role of selenium as a micronutrient in mammals [7]. The reversal of the hydrogen peroxide-induced cell damage mediated by such flavonoids could be observed only in selenium-supplemented, GPx-overexpressing cells, suggesting a direct interplay between flavonoids and the selenium-centered antioxidant system [8]
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