Design, Synthesis And Anti-fibrosis Activity Study Of N-Substituted-Phenylhydroquinolinones Derivatives

Fibrosis is a pathological process involving tissue necrosis due to inflammation, injury, abnormal increase and excessive deposition of extracellular matrix (ECM). Fibrosis can occur in almost all of human organs and tissues, which promote disease progression, increase organ dysfunction.then cause organ failure and eventually death. Therefore, fibrosis diseases seriously threat human life and health and anti-fibrosis therapy is urgently needed to be established for the treatment of these diseases.Pirfenidone (PFD) is the first and the only small molecule anti-fibrosis drugs being in market. PFD was used as multi-target drug and was approved in Japan for the treatment of idiopathic pulmonary fibrosis. In addition, PFD has also been completed in phase II clinical trials for the treatment of fibrosis and multiple sclerosis of the liver, kidney and other organ. However, there are a series of shortcomings, such as weak interaction strength, rapid metabolism and high first pass effect during the application of PFD. Therefore, studies of compounds acting on multi-targets of fibrosis, especially possing better metabolistic, pharmacokinetic and pharmacodynamic profiles will be promising in the field of anti-fibrosis drug research and development.In this study, a kind of PFD derivatives with N-substituted phenyl-hydroquinolinones scaffold was designed and synthesized with pirfenid-one as the leading compound. The chemical structures of 40 N-phenyl substituted hydroquinolinones derivatives were confirmed by MASS, NMR and MS. The anti-fibrosis activity for target compounds were investigated on NIH3T3 fibroblast cell line by MTT method. The preliminary activity results suggest that 33 compounds showed inhibitory activity against cell proliferation and 23 compounds displayed better activity profile than PFD.The structure-activity relationship study of N-substituted phenyl hydroquinolinones derivates indicated that the electron-withdraw substitutents on the aromatic ring at N of phenyl hydroquinolinones is more favorable for the inhibition of cell proliferation. The most potent compound 3j displayed higher activity compared with PFD, with the IC50 of 0.3μM and 4.7μM, respectively and can be used as leading compound for further structure optimization,.In addition, the phenylhydroquinolin-ones scaffold is a good scaffold for the design of more potent anti-fibrosis drugs.In summary, herein we find a new series of compounds with N-substituted phenyl hydroquinolinones scaffold, which show good anti-fibrosis activity and provide a theoretical basis for the discovery of multi-target anti-fibrosis drugs.