Discovery of dihydrothiazolo ring-fused 2-pyridones with extended carboxylic acid as anti-influenza A agents.

Influenza A virus (IAV) infections are a global health concern, aggravated by emerging drug-resistant strains. We report the identification of a series of dihydrothiazolo-ring-fused 2-pyridones bearing an extended carboxylic acid motif as promising antiviral scaffolds. Initial phenotypic screening yielded compound 9 (IC50 = 28 μM), which guided structure-activity optimization at C-6, C-7, and C-8. This yielded compound 35d, which showed moderate potency (IC50 = 21 μM), but with minimal cytotoxicity and a moderate Selectivity Index (∼19). A time-of-addition study indicates that 35d disrupts an early post-attachment stage of the influenza virus life cycle, possibly preventing its entry into the host cell. Notably, 35d also demonstrated broad-spectrum antiviral activity across multiple viral families. A hydroxamic acid bioisostere (74) retained moderate potency, supporting the scaffold's versatility. In silico human ADME/PK predictions for 10 representative analogs indicated favorable properties, including moderate oral bioavailability (≈40-60%), short-moderate half-life (≈2-12 h), CYP2C9-driven metabolism, low plasma unbound fraction (≈0.5-7%), modest tissue distribution, and minor renal/biliary clearance. These findings establish the extended carboxylic-acid 2-pyridone scaffold as a strong foundation for advancing both targeted anti-influenza A agents and broader-spectrum antiviral therapeutics.