School of Pharmaceutical Sciences, Apeejay Stya University, Sohna - Palwal Road, Sohna 122103, India.
Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha 91911, Saudi Arabia.
Molecules. 2020 Apr 25;25(9):2002. doi: 10.3390/molecules25092002.
Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds (IC = 15.50 nM, 114.77%), (IC = 17.50 nM, 101.65%), (IC = 17.10 nM, 104.03%), (IC = 16.90 nM, 105.26%), and (IC = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of , , , , and . These compounds also displayed comparable onset and the duration of action concerning celecoxib and indomethacin in the in vivo studies. No ulcerogenic effects were observed for and , whereas , , and showed an insignificant ulcerogenic effect compared to celecoxib. The compounds , , , , and displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds (%ABS = 84.09), (%ABS = 84.09), (%ABS = 66.87), (%ABS = 75.02), and (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds , , , , and have been recognized and postulated as non-ulcerogenic COX-2 inhibitors with promising physicochemical parameters and gastric safety profile. These compounds may be useful candidates to combat diseases caused by higher levels of COX-2.
环氧化酶-2（COX-2）参与慢性炎症性疾病的发展。最近，哒嗪衍生物已成为开发 COX-2 抑制剂的新型原型。因此，本文报道了一些基于哒嗪的 COX-2 抑制剂。醛和不同的肼反应生成相应的腙。腙进一步衍生为标题化合物，评估它们对 COX-1 和 COX-2 的抑制作用、胃溃疡形成作用和脂质过氧化性质。还进行了分子对接研究和物理化学参数的测定。所分配的化合物结构与其光谱数据一致。报道的化合物的结构与它们的光谱数据一致。化合物 （IC = 15.50 nM，114.77%）、 （IC = 17.50 nM，101.65%）、 （IC = 17.10 nM，104.03%）、 （IC = 16.90 nM，105.26%）和 （IC = 17.70 nM，100.5%）对 COX-2 的抑制作用优于塞来昔布（IC = 17.79 nM，100%）。这些结果与 、 、 、 和 的分子对接研究一致。这些化合物在体内研究中也表现出与塞来昔布和吲哚美辛相当的起效时间和作用持续时间。和 没有观察到溃疡形成作用，而 、 、 和 与塞来昔布相比显示出轻微的溃疡形成作用。化合物 、 、 、 和 表现出比塞来昔布和吲哚美辛更好的脂质过氧化谱。化合物 （%ABS = 84.09）、 （%ABS = 84.09）、 （%ABS = 66.87）、 （%ABS = 75.02）和 （%ABS = 81.42）的计算吸收也明显高于塞来昔布（%ABS = 82.09）。化合物 、 、 、 和 被认为是非溃疡形成的 COX-2 抑制剂，具有有希望的物理化学参数和胃安全性。这些化合物可能是对抗由 COX-2 水平升高引起的疾病的有用候选物。
