The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, these efforts have led to multiple successful vaccines in an exceptionally rapid time frame, as well as the evaluation of a wide range of potential treatments in clinical trials, a few of which have also reached the market. However, vaccines may be less or no effective against emerging variants. Furthermore, effective therapeutic treatments conferring strong attenuation against the virus remain elusive, also considering the development of new variants, the low response to treatment in some patients, and the limits of antiviral drugs, all hindering the effectiveness of the current therapeutic strategies. Therefore, the development of antiviral drugs against SARS-CoV-2 is of paramount importance. Among potential drug targets, the SARS-CoV-2 non-structural protein 13 (nsp13) is highly attractive thanks to its pivotal role in viral replication.1 Nsp13, member of the 1B helicase superfamily, utilizes the energy of nucleotide triphosphate hydrolysis to catalyze the unwinding of double-stranded DNA or RNA in a 5′ to 3′ direction.2 Nonetheless, nsp13 is the most conserved non-structural protein within the CoV family. Moreover, nsp13 has a low mutation rate with only 23 mutations observed in a sample of 439 SARS-CoV-2 viral strains.3 This implies that small molecule nsp13 inhibitors may serve as pan-CoV inhibitors and that previously found compounds targeting nsp13 in other CoVs might be effective against COVID-19. Although the pivotal role of nsp13, there is a paucity of information about small molecules reported in literature as nsp13 inhibitors. Recently, we described a new class of compounds as micromolar inhibitors of both the nsp13-associated activities, active against SARS-CoV-2 replication in cell-based assays.4 Moreover, in silico studies suggested an allosteric binding mode, in agreement with kinetics of inhibition studies that showed their capability of inhibiting the unwinding and the ATPase activities acting non-competitively versus ATP. Noteworthy, they represent the first report of inhibitors active against both the SARS-CoV-2 nsp13-associated activities and capable also of blocking viral replication in SARS-CoV-2 infected cells. Furthermore, the tested compounds proved to be active against high and low pathogenic coronaviruses being MERS-CoV and HCoV 229E, paving the way to the development of pan-CoV inhibitors. Taking advantage of these results, we deepened the structure-activity relationships within this new class of compounds by designing and synthesizing new structural analogues, obtaining new dual SARS-CoV-2 nsp13 ATPase and unwinding inhibitors, also capable of inhibiting viral replication. The data coming from the biological assays will be shown and discussed.