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Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2\/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47\/DF-51 and SARS-CoV-2\/DENV RdRp, respectively, including chelating with Mg2+ near polymerase active site. 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