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 Aug;78:358-371. doi: 10.1016/j.bioorg.2018.03.030. Epub 2018 Apr 3.
New pyrazolo[3,4-d]pyrimidines substituted with various functionalities or attached to a substituted pyrazole ring through different linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity using in vitro COX-1/COX-2 inhibition assay and in vivo formalin induced paw edema and cotton pellet-induced granuloma assays. Results revealed that compounds 17b and 18 possessed COX-1/COX-2 selectivity indices higher than diclofenac sodium and celecoxib. However, compounds 16a,b exhibited selectivity indices higher than diclofenac sodium and nearly equivalent to celecoxib, whereas, 9b displayed selectivity index comparable to diclofenac sodium. In vivo anti-inflammatory data showed that compounds 9b, 16a, 18 displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, the pyrazolyl derivatives 9b, 16b and 17b displayed anti-inflammatory activity about 2-2.5-fold that of diclofenac sodium and nearly 8-10.5-fold that of celecoxib in the cotton pellet-induced granuloma assay. The ulcerogenic effect of the active compounds was also investigated and results revealed that compounds 16a, 17a,b and 18 showed good gastrointestinal safety profile. Based on this, compounds 16a and 18 were considered as safe and effective leads in managing acute inflammation, while, 17b was prominent in controlling chronic inflammation.
合成了具有各种功能取代基的新吡唑并[3,4-d]嘧啶或通过不同键合连接到取代吡唑环的化合物。通过体外 COX-1/COX-2 抑制试验和体内甲醛诱导的爪肿胀和棉绒球诱导的肉芽肿试验评估了合成化合物的抗炎活性。结果表明，化合物 17b 和 18 对 COX-1/COX-2 的选择性指数高于双氯芬酸钠和塞来昔布。然而，化合物 16a,b 表现出高于双氯芬酸钠的选择性指数，接近于塞来昔布，而 9b 则显示出与双氯芬酸钠相当的选择性指数。体内抗炎数据表明，化合物 9b、16a、18 在甲醛诱导的爪肿胀模型中显示出比两种参比物更高的抗炎活性。另一方面，吡唑基衍生物 9b、16b 和 17b 在棉绒球诱导的肉芽肿试验中显示出比双氯芬酸钠高 2-2.5 倍的抗炎活性，比塞来昔布高 8-10.5 倍的抗炎活性。还研究了活性化合物的致溃疡作用，结果表明化合物 16a、17a,b 和 18 具有良好的胃肠道安全性。基于此，化合物 16a 和 18 被认为是治疗急性炎症的安全有效的先导化合物，而 17b 则在控制慢性炎症方面表现突出。
