Abstract
Pirfenidone (5-methyl-1-phenyl-2(1H)-pyridone, PFD) is a small-molecule compound acting on multiple targets involved in pathological fibrogenesis and is effective to increase the survival of patients with fibrosis, such as idiopathic pulmonary fibrosis. However, PFD is not active enough, requiring a high daily dose. In this study, to keep the multiple target profiles, N1-substituted phenylhydroquinolinone derivatives, which retain the 1-phenyl-2(1H)-pyridone scaffold were designed and synthesized. The preliminary anti-fibrosis activities for all target compounds were evaluated on a NIH3T3 fibroblast cell line using MTT assay methods. Most compounds showed significant inhibition on NIH3T3 cell proliferation with a IC50 range of 0.09–26 mM, among which 5-hydroxy-1-(4'-bromophenyl)-5,6,7,8-tetrahydroquinolin-2(1H)-one (6j) displayed 13 times higher potency (IC50 = 0.3 mM) than that of AKF-PD (IC50 = 4.2 mM). These results suggest that N1-substituted phenylhydroquinolinone is a promising scaffold which can be applied for further investigation and for developing novel anti-fibrosis agents.
Highlights
Fibrosis is a pathological process in damaged tissues or organs where fibroblasts are activated to produce and deposit excess extracellular matrix
Accumulating evidence indicates that the mechanisms driving fibrogenesis might be distinct from those regulating inflammation [5]
Fibrogenesis is a complicated process during which mediators including cytokines (IL-13, IL-21, TGF-β1), angiogenic factors (VEGF), growth factors (PDGF) [6], chemokines (MCP-1, MIP-1β), peroxisome proliferator-activated receptors (PPARs) [7], acute phase proteins (SAP) [8], caspases, components of the rennin-angiotensin-aldosterone system (ANG II) [9] and p38 [10] have all been identified as important regulators and are being investigated as potential targets for the development of anti-fibrosis agents [11]
Summary
Fibrosis is a pathological process in damaged tissues or organs where fibroblasts are activated to produce and deposit excess extracellular matrix (mainly composed of collagens). Fibrogenesis is a complicated process during which mediators including cytokines (IL-13, IL-21, TGF-β1), angiogenic factors (VEGF), growth factors (PDGF) [6], chemokines (MCP-1, MIP-1β), peroxisome proliferator-activated receptors (PPARs) [7], acute phase proteins (SAP) [8], caspases, components of the rennin-angiotensin-aldosterone system (ANG II) [9] and p38 [10] have all been identified as important regulators and are being investigated as potential targets for the development of anti-fibrosis agents [11]. To keep the multiple-target anti-fibrosis activity features of PFD and to prevent the rapid metabolism of 5-CH3, the C-5 and C-6 of PFD were cyclized to form an N1-substituted phenylhydroquinolinone scaffold (Figure 2). To evaluate the structure-activity relationship for all target compounds, the in vitro inhibitory activity was measured on NIH3T3 cell lines using MTT methods
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