Jiang Bo, Huang Xiaojing, Yao Hequan, Jiang Jieyun, Wu Xiaoming, Jiang Siyi, Wang Qiujuan, Lu Tao, Xu Jinyi
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China.
Org Biomol Chem. 2014 Apr 7;12(13):2114-27. doi: 10.1039/c3ob41936c. Epub 2014 Feb 24.
A series of hybrids from diaryl-1,2,4-triazole and hydroxamic acid or N-hydroxyurea were synthesized and evaluated as novel anti-inflammatory agents. The biological data showed that (i) all the compounds showed dual COX-2/5-LOX inhibitory activities in vitro, and 15e showed optimal inhibitory activities (COX-2: IC50 = 0.15 μM, 5-LOX: IC50 = 0.85 μM), (ii) 15e selectively inhibited COX-2 relative to COX-1 with selectivity index (SI = 0.012) comparable to celecoxib (SI = 0.015), (iii) 15e exhibited potent anti-inflammatory activity (inhibition: 54.1%) which was comparable to the reference drug celecoxib (inhibition: 46.7%) in a xylene-induced ear edema assay, and (iv) 15e displayed promising analgesic activity in acetic acid-induced writhing response and hot-plate assay. Finally, a molecular modeling study revealed the binding interactions of 15e with COX-2 and 5-LOX. Our findings suggest that 15e may be a promising anti-inflammatory agent for further evaluation.
合成了一系列二芳基-1,2,4-三唑与异羟肟酸或N-羟基脲的杂化物，并将其作为新型抗炎剂进行评估。生物学数据表明：（i）所有化合物在体外均表现出COX-2/5-脂氧合酶双重抑制活性，15e表现出最佳抑制活性（COX-2：IC50 = 0.15 μM，5-脂氧合酶：IC50 = 0.85 μM）；（ii）相对于COX-1，15e选择性抑制COX-2，其选择性指数（SI = 0.012）与塞来昔布相当（SI = 0.015）；（iii）在二甲苯诱导的耳水肿试验中，15e表现出强效抗炎活性（抑制率：54.1%），与参比药物塞来昔布（抑制率：46.7%）相当；（iv）在醋酸诱导的扭体反应和热板试验中，15e显示出有前景的镇痛活性。最后，分子模拟研究揭示了15e与COX-2和5-脂氧合酶的结合相互作用。我们的研究结果表明，15e可能是一种有前景的抗炎剂，值得进一步评估。
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