Design, synthesis and evaluation of novel UDCA-tetrahydropyrazine triazole hybrids for the treatment of pulmonary fibrosis

To discover novel anti-pulmonary fibrosis agents, a series of ursodeoxycholic acid-tetrahydropyrazine triazole hybrids were synthesized through molecular hybridization and scaffold hopping strategies. Their anti-pulmonary fibrosis activities were screened by evaluating their inhibitory effects on TGF-β-induced Collagen deposition in human embryonic lung fibroblast cell (CCC-HPF-1). The results demonstrated that some of the synthesized compounds exhibited potent anti-pulmonary fibrosis effects. Among them, 4w showed the strongest activity (IC₅₀ = 3.21 μM) with no obvious toxicity. The preliminary structure-activity relationship was concluded. Further study showed that 4w significantly reduced the mRNA and protein expression levels of α-SMA, COL1A1 and FN in TGF-β1-induced CCC-HPF-1 cells, and effectively inhibited TGF-β1-induced cell migration. The mechanism studies revealed that 4w exerts anti-pulmonary fibrosis effects by regulating both classical TGF-β/Smad and non-classical Mitogen-Activated Protein Kinase (MAPK) signaling pathways. In summary, our study shows that 4w may be used as a lead compound in the development and research of subsequent anti-pulmonary fibrosis drugs, providing certain data support for the anti-pulmonary fibrosis research of UDCA derivatives.