Rational design, synthesis, and pharmacological properties of pyranochalcone derivatives as potent anti-inflammatory agents

• Published in: European journal of medicinal chemistry Vol. 54; pp. 272 - 280
• Main Authors: Peng, Fei, Wang, Guangcheng, Li, Xiuxia, Cao, Dong, Yang, Zhuang, Ma, Liang, Ye, Haoyu, Liang, Xiaolin, Ran, Yan, Chen, Jinying, Qiu, Jingxiang, Xie, Caifeng, Deng, Chongyang, Xiang, Mingli, Peng, Aihua, Wei, Yuquan, Chen, Lijuan
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-08-2012; Elsevier
• Subjects: Adjuvant-induced arthritis; Animals; Anti-inflammation; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arthritis, Experimental - drug therapy; Benzopyrans - chemical synthesis; Benzopyrans - metabolism; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Biological and medical sciences; Carrageenan - pharmacology; Catalytic Domain; Cell Line; Chalcone - chemical synthesis; Chalcone - metabolism; Chalcone - pharmacology; Chalcone - therapeutic use; Chalcones - chemical synthesis; Chalcones - metabolism; Chalcones - pharmacology; Chalcones - therapeutic use; Chemistry Techniques, Synthetic; Drug Design; Edema - chemically induced; Edema - drug therapy; iNOS; Male; Medical sciences; Mice; Miscellaneous; Molecular Docking Simulation; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - chemistry; Nitric Oxide Synthase Type II - metabolism; NO production; Paw edema; Pharmacology. Drug treatments; Pyranochalcones; Adjuvant-induced arthritis; NO production; iNOS; Paw edema; Pyranochalcones; Anti-inflammation
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.05.005

24 derivatives (5a–x) derived from natural pyranochalcones (I and II) were designed and evaluated for their inhibitory potency on the production of nitric oxide (NO) in LPS-stimulated RAW264.7 cells. Among them, four compounds (5b, 5d, 5f, and 5h) exhibited more potent inhibitory effects on iNOS activity and iNOS-mediated NO production than a positive control indomethacin. Furthermore, 5b could significantly suppress the progression of carrageenan-induced hind paw edema compared to indomethacin at a dosage of 10 mg/kg/day, and dose-dependently ameliorated the development of adjuvant-induced arthritis (AIA) validated by arthritic scores and H&E staining of joints. In addition, docking study confirmed that 5b was an iNOS inhibitor with binding to the active site of murine iNOS.
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► Two natural pyranochalcones and their derivatives were synthesized and evaluated for anti-inflammatory activities. ► 5b showed remarkable in vitro and in vivo anti-inflammatory activity comparable to indomethacin. ► Molecular docking was employed to investigate the binding mode of the significant inhibitor 5b. ► Structure–activity relationship is discussed.