Ligand-Based Pharmacophoric Design and Anti-inflammatory Evaluation of Triazole Linked Semisynthetic Labdane Conjugates.

This study employed a ligand-based pharmacophoric approach to design and synthesize 33 novel semisynthetic labdane-appended triazolyl isatins to discover potential anti-inflammatory agents. The anti-inflammatory efficacy of the derivatives was evaluated by their ability to inhibit the production of NO, TNF-α, and IL-6, in lipopolysaccharide-induced RAW264.7 macrophages. The initial screening revealed that compound ((1-(2-(2,3-dioxoindolin-1-yl)ethyl)-1-1,2,3-triazol-4-yl)methyl ()-3-formyl-5-((1,4a,8a)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-3-enoate) exhibited an anti-inflammatory effect (NO inhibition, IC = 3.13 μΜ), surpassing both the positive control indomethacin (NO inhibition, IC = 7.31 μΜ) and the parent compound labdane dialdehyde. Notably, reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the levels of the anti-inflammatory cytokine IL-10. Mechanistic studies revealed that downregulated the expression of COX-2 and iNOS by inhibiting the NF-κB signaling pathway. In silico molecular modeling studies on NF-κB proteins support these findings, suggesting that is a promising candidate for developing into a potent anti-inflammatory clinical agent.