Design, synthesis, and anti-inflammatory evaluation of forskolin derivatives with mechanistic insights

To address the poor water solubility and insufficient anti-inflammatory activity of forskolin (FSK), the natural diterpene FSK was employed as the parent compound. 11 novel FSK derivatives were synthesised. Evaluation of anti-inflammatory measurement indicated that compound 7 exhibited a good NO inhibition effect with an IC₅₀ value of 5.83 μM and low cytotoxicity, approaching that of the positive control, total L-NMMA. Additionally, it also exhibited excellent inhibitory effects on PGE₂ and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) with IC₅₀ values of 8.31 μM, 7.18 μM, 6.52 μM and 10.11 μM, respectively. Benzoyl derivatives at the C-1 position with hydrazino/amino groups exhibited moderate anti-inflammatory activity, while derivatives with pyridine or dimethylamino side chains showed almost no such activity. Network pharmacology results demonstrated that the target genes of compound 7 were significantly enriched in core inflammatory pathways and covered key biological functions. Molecular docking validation confirmed that compound 7 was bound to the target protein PPARG with a strong binding energy of -8.86 kJ mol^-1. Compound 7 revealed good anti-inflammatory activity via multi-pathway synergy, thereby laying the theoretical foundation for potent agents.