Novel paeonol derivatives: Design, synthesis, and their activity in relieving idiopathic pulmonary fibrosis via the PIM1/p65 pathway

Idiopathic pulmonary fibrosis (IPF) is a common mesenchymal lung disease. Inhibiting of the PIM-1 protein has been identified as a promising therapeutic strategy for IPF. Previous studies have shown that paeonol has certain activity against IPF. To identify more potent compound, a total of 41 novel paeonol-based derivatives were designed, synthesized, and their activity was evaluated by inducing fibrotic phenotypes in NIH-3T3 cells in vitro. Among them, compound B6 demonstrated potent activity (inhibitory rates = 91.2 ± 1.7 %) with low toxicity (viability rate = 99.7 ± 0.42 %). CETSA analysis revealed that it could bind to PIM-1. Further studies indicated that it effectively regulated the production of IPF markers, including Collagen I and α-SMA. In bleomycin (BLM)-induced IPF mice model, it also significantly inhibited the phosphorylation of p65 in lung tissues and influenced the production of SASP factors, including IL-6, IL-1β, and IL-10. These results suggest that compound B6 may serve as a promising lead compound for alleviating the clinical symptoms of IPF.