新型1,2,3-三氮唑类衍生物的合成及抗炎活性研究

Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives

吲哚胺2,3-双加氧酶2(IDO2)在炎症特别是类风湿性关节炎(RA)方面的作用逐渐被阐明,IDO2成为RA治疗的潜在靶点.目前尚未见活性强、选择性高的IDO2小分子抑制剂被报道.以吲哚胺2,3-双加氧酶1(IDO1)抑制剂epacadostat为先导化合物,借助计算机辅助药物设计,设计合成了24个未见文献报道的1,2,3-三氮唑类衍生物.生物活性研究表明,目标化合物均具有IDO1和IDO2酶抑制活性,其中(Z)-N-((1-(2-((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)呋喃-2-甲酰胺(I-11)在100nmol/L浓度下对IDO1和IDO2酶的抑制率分别为76%和49%,优于先导化合物epacadostat(分别为62%和25%).抗炎活性研究表明,化合物I-11可有效抑制脂多糖(LPS)诱导的RAW264.7细胞炎症因子TNF-α的分泌,并且对小鼠耳肿胀抑制率(56.81%,100 mg/kg,灌胃)优于阳性对照Naproxen(45.29%,150 mg/kg,灌胃),表现出较好的抗炎活性.

As the role of indoleamine 2,3-dioxygenase 2(IDO2)in inflammation,especially in rheumatoid arthritis(RA),is gradually being explained,IDO2 has become a potential target for the treatment of RA.No small molecule inhibitor of IDO2with strong activity and high selectivity has been reported yet.With the help of computer-aided drug design,twenty-four 1,2,3-triazole derivatives were designed and synthesized by using epacadostat as a lead compound.The results of biological activity show that all target compounds display the inhibitory effects on IDO1 and IDO2 enzymes.Among them,the inhibition rates of(Z)-N-((1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyformamidine)-1,2,5-oxadiazo-3-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)(I-11)on indoleamine 2,3-dioxygenase 1(IDO1)and IDO2 enzymes were 76%and 49%at 100 nmol/L concentration,respectively,which are better than those of epacadostat(62%and 25%).The anti-inflammatory activity study showed that compound I-11 could significantly inhibit the secretion of inflammatory factor TNF-αat the cellular level.Compound I-11 also showed good in vivo anti-inflammatory activity in mouse ear swelling model,and the inhibition rate was 56.81%at the dose of 100 mg/kg(Ig)which was better than that of naproxen(45.29%,150 mg/kg,Ig).