The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent behind the 2019 global coronavirus pandemic (COVID-19). Even though successful vaccination programs to counteract COVID-19 are available worldwide, little has been accomplished in the development of antivirals to treat the disease. The disparity in COVID-19 vaccination coverage, vaccine resistance, the emergence of SARS-CoV-2 variants of concern, the increased transmission ability and the potential to evade both vaccination and acquired immunity emphasize the relevance of developing antiviral drugs to treat SARS-CoV-2 infections.1 The development of new antiviral agents is, therefore, of utmost importance. The SARS-CoV-2 non-structural protein 13 (nsp13) has been identified as a promising drug target for the development of antivirals due to its pivotal role in viral replication. The CoVs nsp13 is a multidomain enzyme of 601 amino acids that targets the natural nucleotides and deoxynucleotides as substrates when performing its adenosine triphosphatase (ATPase) activity, utilizing the energy of nucleotide triphosphate hydrolysis to unwind DNA or RNA with a 5′-3′ polarity.2 Moreover, nsp13 is the most conserved non-structural protein within the coronavirus family, with a 100% of sequence similarity between SARS-CoV-1 and SARS-CoV-2 nsp13 enzymes.3 Several compounds have been reported to inhibit SARS-CoV-1 nsp13 and, very recently, also SARS-CoV-2 nsp13 has been actively explored as drug target, with some reports describing small molecules as inhibitors of SARS-CoV-2 nsp13. Among them, aryl diketo acids (DKAs), previously described as inhibitors of SARS-CoV-1 nsp13, have been reported as inhibitors also of SARS-CoV-2 nsp13.4 On the other hand, the DKA chain suffers from several limits related to the pharmacokinetic and pharmacodynamic profiles. Therefore, to overcome the limits of the DKA moiety, a variety of compounds were developed by transferring the DKA chain to scaffolds characterized by improved druglike qualities. Therefore, we carried out a semi-random screening on our in-house library of non-DKA derivatives, previously developed to deal out the undesirable DKA properties, identifying a promising hit compound as micromolar nsp13 inhibitor. We synthesized a set of derivatives structurally correlated with the hit, obtaining a new series of dual inhibitors of both the SARS-CoV-2 nsp13-associated activities. The data coming from the biological assays will be shown and discussed.