Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Bioorg Chem. 2018 Oct;80:164-173. doi: 10.1016/j.bioorg.2018.06.013. Epub 2018 Jun 5.
Two new series of pyrazolo[3,4-d]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay. Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs. The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2, 6, 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2, 3d, 3e, 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin.
设计并合成了两个含有噻唑烷酮部分的吡唑并[3,4-d]嘧啶新系列。对新合成的化合物进行了体外（COX-1 和 COX-2）抑制试验评估。对显示出有希望的 COX-2 选择性的化合物进一步进行了体内抗炎筛选，采用福氏完全佐剂诱导的足肿胀（急性模型）和棉绒球诱导的肉芽肿（慢性模型）试验，以塞来昔布和双氯芬酸钠作为参考药物。还确定了组织病理学和溃疡形成潜力。体内抗炎数据表明，化合物 2、6、7d 在福氏完全佐剂诱导的足肿胀模型中显示出比两种对照药物更高的抗炎活性。另一方面，化合物 2、3d、3e、7b 和 7d 在棉绒球诱导的肉芽肿试验中显示出比双氯芬酸钠或与双氯芬酸钠相当的抗炎活性。此外，大多数测试化合物显示出良好的胃肠道安全性。总的来说，化合物 2 和 7d 被认为是治疗急性和慢性炎症的有前途的候选药物，具有安全的胃肠道边际。
