A novel structural class of coumarin-chalcone fibrates as PPARα/γ agonists with potent antioxidant activities: Design, synthesis, biological evaluation and molecular docking studies

• Published in: European journal of medicinal chemistry 2017-09, Vol.138, p.212-220
• Main Authors: Niu, Handong, Wang, Wenbao, Li, Jinyan, Lei, Yu, Zhao, Yong, Yang, Weixu, Zhao, Chaoyue, Lin, Bin, Song, Shaojiang, Wang, Shaojie
• Format: Article
• Language: English
• Subjects: Antioxidant activity; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Chalcones - chemistry; Chalcones - pharmacology; Coumarin-chalcone; Coumarins - chemistry; Coumarins - pharmacology; Dose-Response Relationship, Drug; Drug Design; Fibrates; Fibric Acids - chemical synthesis; Fibric Acids - chemistry; Fibric Acids - pharmacology; Humans; Molecular Docking Simulation; Molecular Structure; PPAR alpha - agonists; PPAR gamma - agonists; PPARα/γ agonists; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.033

A series of structurally interesting coumarin-chalcone fibrates were synthesized and evaluated for their PPARα/γ agonist activities and antioxidant activities. Among these compounds, compounds 5a, 5d, and 7a were identified as potent PPARα and γ dual agonists, and their PPARα agonist activities were found to be more potent than that of Fenofibrate. Furthermore, the results of antioxidant investigations revealed that compounds 5d and 6a−6d had greater potency than Trolox with IC50 values ranging from 9.40 μM to 18.63 μM. The structure–activity relationship revealed that the electron-withdrawing nitro group substituted at the C6′ position of the benzopyran moiety increased the PPARα and γ agonist efficacy. Moreover, the presence of a double bond on the benzopyran moiety was essential for PPARα and γ agonist efficacy. The agonist activity of PPARα exhibited by compound 5d was examined by molecular docking studies. Taken together, the results we obtained showed that compound 5d had the potential to be a lead compound for further research. [Display omitted] •Novel coumarin-chalcone fibrates were synthesized as potent PPAR α/γ agonists.•Compounds 5a, 5d and 7a exhibited potent PPAR α/γ dual agonist activities.•The structure–activity relationships of the synthesized compounds were summarized.•Molecular docking studies were performed.