Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy.
Kizhner Research Center, National Research Tomsk Polytechnic University, Tomsk 634050, Russia.
Molecules. 2024 May 21;29(11):2421. doi: 10.3390/molecules29112421.
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-]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 (IC < 50 µM) in a cell-based test system, with two of the most potent being compounds (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-]quinazoline-3-carboxamide) and (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that and may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and -Jun -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 and 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-]quinazoline and related scaffolds that are targeted toward MAPKs.
慢性炎症会导致许多疾病。因此，控制炎症反应是一个重要的治疗目标。为了鉴定新的抗炎化合物，我们合成并筛选了 80 个吡唑并[1,5-a]喹唑啉化合物及其相关衍生物文库。在人类 THP-1Blue 单核细胞中筛选这些化合物抑制脂多糖 (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 (IC < 50 µM) 的化合物，其中两种最有效的化合物是化合物 (5-[(4-磺酰胺基苄基)氧基]吡唑并[1,5-a]喹唑啉-3-甲酰胺) 和 (5-[(4-(甲亚磺酰基)苄基)氧基]吡唑并[1,5-a]喹唑啉-3-甲酰胺)。潜在靶标的药效团映射预测 和 可能是三种丝裂原活化蛋白激酶 (MAPKs) 的配体，包括细胞外信号调节激酶 2 (ERK2)、p38α 和 -Jun 末端激酶 3 (JNK3)。事实上，分子建模支持这些化合物可以有效地与 ERK2、p38α 和 JNK3 结合，与 JNK3 的互补性最高。确定了 JNK3 中对这种结合很重要的关键残基。此外，化合物 和 对 JNK1、JNK2 和 JNK3 具有微摩尔结合亲和力。因此，我们的结果表明，基于吡唑并[1,5-a]喹唑啉和相关支架开发针对 MAPKs 的新型抗炎先导药物具有潜力。
