Development of Benzimidazole-Based BZ-30 as an Orally Bioavailable Broad-Spectrum Inhibitor of SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of the 2019 global pandemic, continues to undermine therapeutic interventions due to its high transmissibility and mutability. This highlights the need for potent antivirals capable of combating emerging variants and controlling outbreaks. Here, we report the discovery and development of the first-in-class novel benzimidazole (BZ) derivatives as potent inhibitors of SARS-CoV-2. Through antiviral screening, the benzimidazolone derivative (I) was found as the hit. Further hit-to-lead optimization led to BZ compounds with submicromolar IC₅₀ values. Mechanistically, these compounds partially inhibit endocytosis entry pathways. The compounds shortlisted have broad-spectrum antiviral profiles against different variants of concern. Notably, BZ-01 and BZ-30 show good pharmacokinetic properties, with BZ-30 displaying excellent oral bioavailability. Evaluation of BZ-30 in SARS-CoV-2-challenged hamsters significantly reduced viral load and improved lung pathology, indicating its in vivo antiviral efficacy and highlighting its therapeutic potential as an orally available antiviral candidate.