Pyridobenzothiazolones as non-nucleoside antivirals: from HCV polymerase inhibition to broad-spectrum antiviral agents

Pyridobenzothiazolones (PBTZs) are tricyclic compounds originally investigated as chemotypes directed against viral RNA-dependent RNA polymerases. Following the first reports on hepatitis C virus (HCV) NS5B inhibition, medicinal chemistry optimization and mechanistic studies have expanded the antiviral profile of this scaffold to the inhibition of flaviviruses (including Dengue, Zika, West Nile viruses) and, most recently, of respiratory RNA viruses including human coronaviruses, respiratory syncytial viruses and influenza viruses. This review summarizes the PBTZ chemical series, covering structure–activity relationships, proposed mechanisms of action, antiviral potency ranges, pharmacological limitations, and prospects for clinical development. The available evidence supports PBTZs as a chemically versatile platform capable of engaging both viral enzymes and virion-associated processes, positioning this scaffold as a promising platform for next-generation broad-spectrum antiviral therapeutics.