1. Academic Validation
  2. Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis

Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis

  • Eur J Med Chem. 2024 Jun 5:272:116487. doi: 10.1016/j.ejmech.2024.116487.
Xiaobo Li 1 Xinyi Huang 2 Yunxi Zhao 3 Zhiwei Zheng 3 Mi Guo 3 Zhicao Chen 3 Pan Chen 3 Xiang Li 3 Jing Liao 3 Miao Jiang 4 Won-Jea Cho 5 Young-Chang Cho 5 Ruifeng Zeng 6 Qidong Tang 7 Guang Liang 8
Affiliations

Affiliations

  • 1 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial Peoples Hospital, Affiliated Peoples Hospital, Hangzhou Medical College, Hangzhou, 310014, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Department of Nursing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 4 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, 325035, China.
  • 5 College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 6 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: ruifengzeng@163.com.
  • 7 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: tangqidongcn@126.com.
  • 8 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial Peoples Hospital, Affiliated Peoples Hospital, Hangzhou Medical College, Hangzhou, 310014, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. Electronic address: wzmcliangguang@163.com.
Abstract

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 μM and 6.51 μM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.

Keywords

4-Hydroxycoumarin derivatives; Acute lung injury; Anti-inflammatory; Colitis; IRAK1; MAPK.

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