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

化学 炎症性肠病 结肠炎 IC50型 体内 急性毒性 药代动力学 对接(动物) 药理学 毒性 体外 生物化学 免疫学 医学 疾病 生物 生物技术 有机化学 护理部 病理
作者
Xiaobo Li,Xinyi Huang,Yunxi Zhao,Zhiwei Zheng,Mi Guo,Z. Chen,Pan Chen,Xiang Li,Jing Liao,Miao Jiang,Won-Jea Cho,Young-Chang Cho,Ruifeng Zeng,Qidong Tang,Guang Liang
出处
期刊:European journal of medicinal chemistry [Elsevier]
卷期号:272: 116487-116487
标识
DOI:10.1016/j.ejmech.2024.116487
摘要

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.
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