Zhang Yali, Xu Zhengwei, Zhan Lingling, Gao Yi, Zheng Bin, Zhou Yan, Sheng Yaoguang, Liang Guang, Song Zengqiang
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Bioorg Chem. 2022 Nov;128:106049. doi: 10.1016/j.bioorg.2022.106049. Epub 2022 Jul 25.
Acute lung injury (ALI) is an acute inflammatory disease, which severely impacts lung function with a high lethality rate. Chromone and maleimide are very important moieties of anti-inflammatory agents. Here, forty new chromone-maleimide hybrids were readily synthesized using a Heck-type coupling strategy in good yields and were screened for their anti-inflammatory activity. A majority of these hybrids showed high inhibitory potency against LPS-stimulated release of pro-inflammatory cytokines in macrophages. Preliminary structure-activity relationship studies led to the discovery of highly potent inhibitors. Five of them were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner with IC values in the nanomolar rang. Furthermore, in vivo administration of 5e and 5g resulted in distinctly attenuated LPS-induced ALI via inhibiting the inflammation. Thus it is evident from our study that these novel chromone-maleimide hybrids present promising therapeutic potential for ALI.
急性肺损伤（ALI）是一种急性炎症性疾病，严重影响肺功能，致死率高。色酮和马来酰亚胺是抗炎剂的非常重要的部分。在此，使用Heck型偶联策略以良好的产率轻松合成了40种新的色酮-马来酰亚胺杂化物，并对其抗炎活性进行了筛选。这些杂化物中的大多数对巨噬细胞中LPS刺激的促炎细胞因子释放显示出高抑制效力。初步的构效关系研究导致发现了高效抑制剂。其中五种被发现以剂量依赖性方式抑制脂多糖（LPS）诱导的IL-6和TNF-α释放，IC值在纳摩尔范围内。此外，体内给予5e和5g通过抑制炎症导致LPS诱导的ALI明显减轻。因此，从我们的研究中可以明显看出，这些新型色酮-马来酰亚胺杂化物对ALI具有有前景的治疗潜力。
