Department of Chemistry, Faculty of Science Girls, Al-Azhar University, Nasr City, Cairo, 11754, Egypt.
Department of Chemistry, Faculty of Science Boys, Al-Azhar University, Nasr City, Cairo, 11884, Egypt.
Eur J Med Chem. 2023 Mar 5;249:115138. doi: 10.1016/j.ejmech.2023.115138. Epub 2023 Jan 19.
Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2-13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC values of 5.68 ± 0.08 and 3.37 ± 0.07 μM compared with celecoxib (IC = 3.60 ± 0.07 μM) and meloxicam (IC = 7.58 ± 0.13 μM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.
寻找具有抗炎特性的新化合物是一个重要的目标，因为炎症是疼痛的主要原因。通过 3,5-二氨基-1H-吡唑衍生物与环状和非环状羰基试剂的反应，设计并合成了一系列吡唑、咪唑并吡唑酮和吡唑并嘧啶衍生物。新合成衍生物的结构完全通过不同的光谱数据和元素分析进行了表征，并因此被评估为 COX-2 抑制剂。测试衍生物 2-13 的体外 COX-2 活性显示出中等至良好的效力，其中两个衍生物 8 和 13 对 COX-2 具有高效力，IC 值分别为 5.68 ± 0.08 和 3.37 ± 0.07 μM，与塞来昔布（IC = 3.60 ± 0.07 μM）和美洛昔康（IC = 7.58 ± 0.13 μM）相比。此外，最活跃的吡唑并[1,5-a]嘧啶衍生物 8 和 13 用于测量 RAW264.7 细胞中促炎蛋白（如 TNF-α 和 IL-6）的水平，结果显示两种免疫调节蛋白下调。令人惊讶的是，与塞来昔布（% = 76.8）相比，这些衍生物 8 和 13 分别使 IL-6 水平降低了 65.8%和 70.3%。此外，化合物 8 和 13 可以调节和抑制 TNF-α，对对照的抑制率分别为 63.1%和 59.2%，而塞来昔布显示抑制率为 72.7%。进行了量子化学计算，数据解释了对活性至关重要的结构特征。分子对接模拟和 ADMET 预测表明，最活跃的衍生物具有良好的结合亲和力，具有适当的类药性和低毒性特征。最后，化合物 8 和 13 表现出 COX-2 抑制剂的特性，具有抑制 α-TNF 和 IL-6 的能力，作为一种双重作用策略，以获得更有效的治疗效果。
