1,5-二芳基取代-1,2,4-三唑类衍生物的合成、抗炎活性及其构效关系研究  

Synthesis,anti-inflammatory activities and SAR studies of 1,5-diarylsubstituted-1,2,4-triazoles

作　　者：徐进宜[1] 曾翼[1] 江波[1] 付立志[1] 朱林荣[1] 张晓栋[1] 吴晓明[1] 华维一[1] 王秋娟[2] 贾莹[2] 杨丰[2] 

机构地区：[1]中国药科大学药物化学教研室,江苏南京210009 [2]中国药科大学生理学教研室,江苏南京210009

出　　处：《中国药物化学杂志》2008年第5期321-328,共8页Chinese Journal of Medicinal Chemistry

基　　金：教育部优秀青年教师基金项目(2003355);江苏省自然科学基金项目(BK2004109)

摘　　要：目的寻找高活性的选择性环氧合酶-2抑制剂,探讨其构效关系。方法根据已上市的选择性环氧合酶-2抑制剂celecoxib的构效关系以及分子模拟研究的结果,设计了两类1,5-二芳基取代-1,2,4-三唑类衍生物,以1-(4-取代苯基)-3-硫代氨基脲为原料,经多步反应合成目标化合物;用小鼠二甲苯致炎模型对目标化合物进行体外抗炎活性测试。结果与结论合成了22个未见文献报道的新化合物,所有目标化合物的结构经IR、1H-NMR、MS谱和元素分析确证。生物活性研究表明,化合物I3、I9、I12、I15、II2、II3、II6、II7具有较强的抗炎活性(P<0.01),其中化合物II2、II3、II6的抗炎活性最强。构效关系分析发现,在三唑环1位芳基的对位引入F、Cl、Br吸电子基团以及3位引入磺酰基和甲硫基,对抗炎活性有重要的意义;在三唑环5位芳基的对位引入氨磺酰基,对抗炎活性有较大影响。Aim To search for selective cyclooxygenase-2（COX-2） inhibitors with high potency and less side effects and to study the structure-activity relationships（SAR） of the title compounds. Methods Based on the SAR of celecoxib and related molecular modeling studies, twenty, two 1, 5-diarylsubstituted-1, 2, 4-triazole derivatives were designed and synthesized. The inhibitory effect of target compounds on xylene-induced mice ear swelling model were determined. Results and conclusion The structures of target compounds were confirmed by IR, ^1H-NMR, MS spectra and elemental analysis. The results of pharmacological test in vitro show that eight compounds I3, 19, I12,115, II2, II3, II6 and 117 have potent anti-inflammatory activity（ P 〈 0.01）, while compounds 112,113 and II6 exhibit marked potency. The analysis of SAR reveals that the activities of target compounds are closely associated with the electron-withdrawing substituents （F, C1, Br） at the para position of 1-aryl-1, 2, 4-triazoles as well as with the substituents such as sulfonyl and methylthio groups at the 3 position of 1,2, 4-triazoles;And the introduction of sulfamoyl moiety at the para position of 5-aryl-1,2, 4-triazoles also has significant influence on the anti-inflammatory activity of these compounds.

关 键 词：环氧合酶-2抑制剂 1 2 4-三唑 化学合成 抗炎活性 构效关系 

分 类 号：R914[医药卫生—药物化学]