Design, synthesis and anti-influenza A virus activity of N-containing heterocyclic glycyrrhetinic acid derivatives

Glycyrrhetinic acid (GA), a bioactive triterpenoid derived from Glycyrrhiza glabra, exhibits broad-spectrum Antiviral properties but suffers from poor solubility and bioavailability. To enhance its anti-influenza activity, we designed and synthesized 12 novel nitrogen-containing heterocyclic GA derivatives through structural modifications at the A-ring (C-2/C-3) and C-30 position. All compounds were evaluated against influenza A/H1N1 virus in 293T cells. At 10 μM, 10 derivatives outperformed ribavirin, with compound 12b (bearing an A-ring furazan and C-30 imidazole ester) showing the highest potency (IC₅₀ = 2.9 μM, selectivity index SI = 38.6) representing a 7.1-fold improvement over GA (IC₅₀ = 9.6 μM) and 3.7-fold superiority to ribavirin. Molecular docking revealed that 12b binds strongly to neuraminidase (PDB:1NN2; binding energy: -8.11 kcal/mol) via hydrogen bonds with Glu413, Asp125, and Phe100, suggesting NA as a potential target. This study demonstrates that A-ring furazan modification combined with C-30 nitrogen-containing heterocyclic incorporation significantly enhances anti-influenza activity, providing a promising lead compound (12b) for further development.