PDF(Pubmed)
Abstract：
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-a]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC50 < 50 µM) in a cell-based test system, with two of the most potent being compounds 13i (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-a]quinazoline-3-carboxamide) and 16 (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-a]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that 13i and 16 may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and c-Jun N-terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds 13i and 16 exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-a]quinazoline and related scaffolds that are targeted toward MAPKs.
摘要：
慢性炎症导致许多疾病。因此,控制炎症反应是一个重要的治疗目标。为了鉴定新型抗炎化合物，我们合成并筛选了80个吡唑并[1,5-a]喹唑啉化合物及相关衍生物的文库。筛选这些化合物抑制人THP-1Blue单核细胞中脂多糖（LPS）诱导的核因子κB（NF-κB）转录活性的能力，在基于细胞的测试系统中鉴定出13种具有抗炎活性（IC50<50µM）的化合物，其中最有效的两个是化合物13i(5-[(4-氨磺酰基苄基)氧基]吡唑并[1,5-a]喹唑啉-3-甲酰胺)和16(5-[(4-(甲基亚磺酰基)苄氧基]吡唑并[1,5-a]喹唑啉-3-甲酰胺)。潜在靶标的药效团作图预测13i和16可能是三种丝裂原活化蛋白激酶（MAPK）的配体，包括细胞外信号调节激酶2（ERK2），p38α,和c-JunN末端激酶3(JNK3)。的确,分子模型支持这些化合物可以有效地结合ERK2，p38α，和JNK3，与JNK3的互补性最高。鉴定了对该结合重要的JNK3的关键残基。此外，化合物13i和16表现出对JNK1、JNK2和JNK3的微摩尔结合亲和力。因此，我们的结果证明了开发基于吡唑并[1,5-a]喹唑啉和靶向MAPK的相关支架的主要抗炎药的潜力。
