Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and 
interstitial lung disease with the median survival of only 3-5 years. However, 
due to the unclear etiology and problems in accurate diagnosis, up to now only 
two drugs were approved by FDA for the treatment of IPF and their outcome 
responses are limited. Numerous studies have shown that TGF-β is the most 
important cytokine in the development of pulmonary fibrosis and plays a role 
through its downstream signaling molecule TGF-binding receptor Smads protein. In 
this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their 
anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as 
the most active one and could inhibit TGF-β-induced collagen deposition of 
NRK-49F cells and mouse fibroblasts migration with comparable activity and lower 
cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 
20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen Ⅰ 
by inhibiting the TGF-β/Smad dependent pathways and ERK1/2 and p38 pathways. 
Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more 
effectively alleviated collagen deposition in lung tissue and delayed the 
destruction of lung tissue structure both in bleomycin-induced prevention and 
treatment mice pulmonary fibrosis models. The immunohistochemical experiments 
further showed that 20f could block the expression level of phosphorylated Smad3 
in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. 
In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare 
with nintedanib) and an appropriate elimination half-life (T1/2 = 3.5 h), 
suggesting that 20f may be a potential drug candidate for the treatment of 
pulmonary fibrosis.