Abstract：
Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1β. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.
摘要：
与吲哚美辛和塞来昔布相比，合成了五个新的吖嗪支架，并评估了其对环氧合酶1（COX-1）和环氧合酶2（COX-2）的抑制潜力。大多数合成的化合物显示出明确的COX-2优于COX-1抑制。化合物4c和6b对COX-2酶表现出增强的效力，IC50值为0.26和0.18μM，分别,与塞来昔布相比，IC50=0.35µM。化合物6b的选择性指数（SI）为6.33，高于吲哚美辛（SI=0.50），表明最主要的COX-2抑制活性。因此,化合物6b的体内抗炎活性与吲哚美辛和塞来昔布相当，口服化合物6b后未检测到溃疡性作用。如组织病理学检查所示。此外，化合物6b降低血清血浆PEG2和IL-1β。为了合理化COX-2抑制的选择性和效力，进行化合物6b进入COX-2活性位点的分子对接研究。化合物6b的COX-2抑制和选择性可归因于其进入COX-2酶的侧袋并与必需氨基酸His90相互作用的能力。一起,这些发现表明,化合物6b是可能设计COX-2抑制剂的有前景的线索,这些抑制剂可用作安全有效的抗炎药.
