T from the original supply. These permissions are granted free of charge by Elsevier for so long as the COVID-19 resource centre remains active.European Journal of Medicinal Chemistry 225 (2021)Contents lists readily available at ScienceDirectEuropean Journal of Medicinal Chemistryjournal COX-1 Inhibitor web homepage: http://www.elsevier.com/locate/ejmechDiscovery of juglone and its derivatives as potent SARS-CoV-2 main 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 type eight August 2021 Accepted 15 August 2021 Offered on the net 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) from the virus as the big enzyme processing viral polyproteins IP Activator Storage & Stability contributed for 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 had been prepared and evaluated for the inhibitory efficacy against SARS-CoV-2 Mpro. More than half from the tested naphthoquinones could efficiently inhibit the target enzyme with an inhibition rate of more than 90 at the concentration of ten mM. In the structure-activity relationships (SARs) analysis, the traits of substituents and their position on juglone core scaffold were recognized as important ingredients for enzyme inhibitory activity. One of the most active compound, 2-acetyl-8-methoxy-1,4-naphthoquinone (15), which exhibited a lot larger potency in enzyme inhibitions than shikonin because the good control, displayed an IC50 worth of 72.07 4.84 nM towards Mpro-mediated hydrolysis from the fluorescently labeled peptide. It fit effectively into the active web site cavity of the enzyme by forming hydrogen bonds with adjacent amino acid residues in molecular docking studies. The outcomes from in vitro antiviral activity evaluation demonstrated that one of the most potent Mpro inhibitor could significantly suppress the replication of SARS-CoV-2 in Vero E6 cells inside the low micromolar concentrations, with its EC50 worth of about four.55 mM. It was non-toxic towards the host Vero E6 cells under tested concentrations. The present study perform 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 actually a really serious infectious illness triggered by a brand new coronavirus named extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2]. The fast spread of this pneumonia disease is definitely an ongoing worldwide threat that generates over 197 million diagnosed circumstances and more than four.21 million deaths over 233 nations and territories globally by 03 Aug 2021 [3]. Till now, no clinically specific antiviral chemotherapeutics were available to treat the illness. The authorized chemotherapeutic drugs against COVID-19 integrated favipiravir [4], lopinavir/ritonavir [5], chloroquine/hydroxychloroquine (FDA revoked emergency use authorization for chloroquine and hydroxychloroquine on June 15, 2020) [6], and remdesivir [7,8]. All of those drugs had been created for the therapy of other related viruses, including SARS and MERS coronavirus, Ebola, and HIV. Their degree of efficacy in Corresponding authors. E-mail addr.