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Background: This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents. Objective: Antiretroviral therapy induces oxidative stress. Based on this, the main objective of this manuscript is the preparation of compounds that combine anti-HIV and antioxidant activities. Methods: The compounds were prepared from commercially available AZT, through a copper-catalyzed Huisgen 1,3-dipolar cycloadditions exploiting the AZT azide group and chalcogenyl alkynes. Results: The chalcogenium-AZT derivatives were obtained in good yields via click chemistry. The compounds evaluated showed antioxidant and anti-HIV activity. Additionally, in vivo toxicity of this class of compounds was also evaluated and the representative nucleoside did not change the survival, behavior, biochemical hepatic, and renal markers compared to the control mice. Conclusion: Data suggest the feasibility of modifying the AZT nucleus with simple organochalcogen fragments, exploring the reactivity of the azide group via 1,3-dipolar Huisgen cycloaddition reaction. The design of these new compounds showed the initially desired biological activities.

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, This work was supported by the University of Perugia “Fondo per la Ricerca di Base 2019”(C.S.); Fundación hna (to A.V.C. and O.A.); Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017 to O.A.); Fondo de Investigaciones Sanitarias from the Instituto de Salud Carlos III, and the European Union (ERDF/ESF, “Investing in your future”) (PI18/00349 to O.A. and an FIS Research Contract to L.C.L.); Spanish Ministry of Economy and Competitiveness (BFU2016-78232-P to A.V.C.); Spanish Ministry of Science, Innovation and Universities (FPI Predoctoral Research Contract BES-2017-080739 to D.O.A.); Diputación General de Aragón (Predoctoral Research Contract 2019 to A.J.A., “Protein Targets and Bioactive Compounds Group” E45_20R to A.V.C., “Digestive Pathology Group” B25_20R to O.A.); and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. FAPERGS, CNPq, and FINEP are acknowledged for financial support. CNPq is also acknowledged for fellowships to E.J.L. and D.A. This work was supported by the subsidy from the Polish Ministry of Science and Higher Education for research on the