Coronaviruses (CoVs) have continuously posed a threat to human and animal health. However, existing antiviral drugs are still insufficient in overcoming the challenges caused by multiple strains of CoVs. And methods for developing multi-target drugs are limited in terms of exploring drug targets with similar functions or structures. In this study, four rounds of structural design and modification on salinomycin were performed for novel antiviral compounds. It was based on the strategy of similar topological structure binding properties of protein targets (STSBPT), resulting in the high-efficient synthesis of the optimal compound M1, which could bind to aminopeptidase N and 3C-like protease from hosts and viruses, respectively, and exhibit a broad-spectrum antiviral effect against severe acute respiratory syndrome CoV 2 pseudovirus, porcine epidemic diarrhea virus, transmissible gastroenteritis virus, feline infectious peritonitis virus and mouse hepatitis virus. Furthermore, the drug-binding domains of these proteins were found to be structurally similar based on the STSBPT strategy. The compounds screened and designed based on this region were expected to have broad-spectrum and strong antiviral activities. The STSBPT strategy is expected to be a fundamental tool in accelerating the discovery of multiple targets with similar effects and drugs.