T of the original source. These permissions are granted totally free by Elsevier for as long as the COVID-19 resource centre remains active.European Journal of Medicinal Chemistry 225 (2021)Contents lists accessible at ScienceDirectEuropean Journal of Medicinal Chemistryjournal homepage: http://www.elsevier.com/locate/ejmechDiscovery of juglone and its derivatives as potent SARS-CoV-2 principal proteinase inhibitorsJiahua Cui, Jinping JiaSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, Chinaa r t i c l e i n f oArticle history: Received 27 April 2021 Received in revised form eight August 2021 Accepted 15 August 2021 Available online 18 August 2021 Keywords: Naphthoquinones Juglone Mpro inhibitors SARS-CoV-2 COVID-a b s t r a c tSARS-CoV-2 as a positive-sense single-stranded RNA coronavirus caused the international outbreak of COVID19. The key protease (Mpro) of your virus as the big enzyme D4 Receptor Agonist Purity & Documentation processing viral polyproteins contributed towards the replication and transcription of SARS-CoV-2 in host cells, and has been characterized as an eye-catching target in drug discovery. Herein, a set of 1,4-naphthoquinones with juglone skeleton were prepared and evaluated for the inhibitory efficacy against SARS-CoV-2 Mpro. Greater than half in the tested naphthoquinones could proficiently inhibit the target enzyme with an inhibition price of more than 90 in the concentration of ten mM. Within the structure-activity relationships (SARs) evaluation, the qualities of substituents and their position on juglone core scaffold were recognized as key components for enzyme inhibitory activity. The most active compound, 2-acetyl-8-methoxy-1,4-naphthoquinone (15), which exhibited considerably greater potency in enzyme inhibitions than shikonin as the good manage, displayed an IC50 value of 72.07 4.84 nM towards Mpro-mediated hydrolysis of the fluorescently labeled peptide. It match properly into the active web page cavity of the enzyme by forming hydrogen bonds with adjacent amino acid residues in molecular docking research. The results from in vitro antiviral activity evaluation demonstrated that by far the most potent Mpro inhibitor could considerably suppress the replication of SARS-CoV-2 in Vero E6 cells within the low micromolar concentrations, with its EC50 value of about 4.55 mM. It was non-toxic towards the host Vero E6 cells below tested concentrations. The present analysis operate FGFR4 Inhibitor web implied that juglone skeleton might be a main template for the development of potent Mpro inhibitors. 2021 Elsevier Masson SAS. All rights reserved.1. Introduction Coronavirus illness 2019 (COVID-19) is a really serious infectious disease brought on by a new coronavirus named severe acute respiratory syndrome coronavirus two (SARS-CoV-2) [1,2]. The speedy spread of this pneumonia illness is an ongoing global threat that generates over 197 million diagnosed cases and more than four.21 million deaths over 233 countries and territories globally by 03 Aug 2021 . Until now, no clinically precise antiviral chemotherapeutics have been accessible to treat the disease. The approved chemotherapeutic drugs against COVID-19 incorporated favipiravir , lopinavir/ritonavir , chloroquine/hydroxychloroquine (FDA revoked emergency use authorization for chloroquine and hydroxychloroquine on June 15, 2020) , and remdesivir [7,8]. All of these drugs had been developed for the therapy of other associated viruses, like SARS and MERS coronavirus, Ebola, and HIV. Their degree of efficacy in Corresponding authors. E-mail addr.