Abstract：
Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03-0.06 μM, SI = 282.7-472.9) with high activity against 5-LOX (IC50 = 4.36-4.86 μM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 μM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.
摘要：
片段合并方法用于噻唑/噻唑烷酮簇状吡唑啉衍生物5a-e的设计，6a-c,7和10a-d作为双重COX-2和5-LOX抑制剂。化合物5a,a.和6b是最有效的COX-2选择性抑制剂（IC50=0.03-0.06μM，SI=282.7-472.9）对5-LOX具有高活性（IC50=4.36-4.86μM），而化合物5b和10a是活性和选择性的5-LOX抑制剂，IC50=2.43和1.58μM，分别。对大多数活性候选物6a的体内测定和组织病理学检查显示,与标准药物相比,炎症显著减少,具有更高的安全性。化合物6a表现出与参考COX-2和5-LOX抑制剂相同的方向和结合相互作用（塞来昔布和槲皮素，分别)。因此,化合物6a已被确定为进一步优化和开发安全有效的抗炎药的潜在线索。
