Design, Synthesis, and Structure-Activity Relationship Analysis of Thiazolo[3,2-a]pyrimidine Derivatives with Anti-inflammatory Activity in Acute Lung Injury
Design, Synthesis, and Structure-Activity Relationship Analysis of Thiazolo[3,2-a]pyrimidine Derivatives with Anti-inflammatory Activity in Acute Lung Injury
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具有急性肺损伤抗炎活性的噻唑并[3,2-a]嘧啶衍生物的设计、合成及构效关系分析
DOI：
10.1002/cmdc.201700175
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发表时间：
2017-07-06
期刊：
影响因子：
3.4
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Lingfeng;Jin, Yiyi;Liang, Guang
急性肺损伤（ALI）具有高致死率，并且白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）在ALI病例中对组织恶化贡献最大。在本研究中，我们设计并合成了一系列新的噻唑并[3，2-a]嘧啶衍生物的基础上，以前确定的先导化合物，我们评估了它们的抗炎活性。结构-活性关系研究导致发现了两种高效抑制剂。发现这两种有前途的化合物以剂量依赖性方式抑制脂多糖（LPS）诱导的小鼠原代腹腔巨噬细胞（MPM）中IL-6和TNF-α的释放。此外，这些化合物的给药导致肺组织病理学改善和体内LPS诱导的ALI减弱。综上所述，这些数据表明，这些新的噻唑并[3，2-a]嘧啶衍生物可以被开发为用于治疗ALI的候选药物。
Acute lung injury (ALI) has a high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[ 3,2-a] pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti-inflammatory activities. Structure-activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-a release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS-induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2-a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI.