Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice
- Eur J Med Chem. 2021 Mar 5:213:113162. doi: 10.1016/j.ejmech.2021.113162.
- 1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.
- 2. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.
- 3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China.
- 4. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230032, Anhui, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China. Electronic address: [email protected].
- 5. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China. Electronic address: [email protected].
Based on the previous research results of our research group, to further improve the anti-inflammatory activity of hesperetin, we substituted triazole at the 7-OH branch of hesperetin. We also evaluated the anti-inflammatory activity of 39 new hesperetin derivatives. All compounds showed inhibitory effects on nitric oxide (NO) and inflammatory factors in lipopolysaccharide-induced RAW264.7 cells. Compound d5 showed a strong inhibitory effect on NO (half maximal inhibitory concentration = 2.34 ± 0.7 μM) and tumor necrosis factor-α, interleukin (IL)-1β, and (IL-6). Structure-activity relationships indicate that 7-O-triazole is buried in a medium-sized hydrophobic cavity that binds to the receptor. Compound d5 can also reduce the Reactive Oxygen Species production and significantly inhibit the expression of inducible NO Synthase and cyclooxygenase-2 through the nuclear factor-κB signaling pathway. In vivo results indicate that d5 can reduce liver inflammation in mice with acute liver injury (ALI) induced by CCI4. In conclusion, d5 may be a candidate drug for treating inflammation associated with ALI.