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 <b>7</b> 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-<i>α</i>, IL-6 and IL-1<i>β</i>) 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 <b>7</b> were significantly enriched in core inflammatory pathways and covered key biological functions. Molecular docking validation confirmed that compound <b>7</b> was bound to the target protein PPARG with a strong binding energy of -8.86 kJ mol^-1. Compound <b>7</b> revealed good anti-inflammatory activity <i>via</i> multi-pathway synergy, thereby laying the theoretical foundation for potent agents.