Coumarin-derived oxadiazoles as potential antiviral agents against coronaviruses

Coronaviruses continue to pose a threat to human and animal health, as demonstrated by the SARS-CoV-2 pandemic and the persistent circulation of endemic and avian coronaviruses. While vaccination remains central to disease prevention, the emergence of viral variants, limited therapeutic options, and the potential for Antiviral resistance emphasise the need for new, broad-spectrum Antiviral agents. In this study, a series of oxadiazole derivatives of 4-hydroxycoumarin were synthesised, characterised, and evaluated for Antiviral activity against human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and infectious bronchitis virus (IBV). The synthesised compounds demonstrated favourable cytotoxicity profiles and exhibited Antiviral activity across multiple experimental systems. The derivatives significantly reduced HCoV-OC43 replication and viral nucleocapsid protein expression in infected cells, accompanied by reduced expression of pro-inflammatory cytokines. In the ex ovo IBV embryo model, compound treatment reduced viral RNA levels and improved embryo survival. Among the tested compounds, compound 4a exhibited the strongest Antiviral activity and inhibited SARS-CoV-2 Infection in immunofluorescence-based assays. Biochemical analyses and in silico molecular docking simulations revealed that compound 4a targets the viral main protease active site, supporting a hypothesised mechanism involving disruption of coronavirus replication-associated processes. Coupled with a favourable in silico pharmacokinetic and ADMET profile, these findings identify coumarin-based oxadiazole derivatives as promising anti-coronavirus scaffolds and support advancing this lead candidate to in vivo preclinical evaluation.