Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-ami de derivatives as anti-inflammatory agents
Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-ami de derivatives as anti-inflammatory agents
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新型合成 5-烷基-4-氧代-4,5-二氢-[1,2,4]三唑并[4,3-a]喹喔啉-1-羧酰胺衍生物作为抗炎剂的发现和评价
DOI：
10.1080/14756366.2019.1680658
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发表时间：
2020
影响因子：
5.6
通讯作者：
Quan Zhe-Shan
中科院分区：
文献类型：
--
作者：
Shen Qing-Kun;Gong Guo-Hua;Li Gao-;Jin Mei;Cao Li-Hua;Quan Zhe-Shan
为了开发新型抗炎药，设计、合成了一系列5-烷基-4-氧-4,5-二氢-[1,2,4]三唑[4,3-a]喹诺啉-1-羧酰胺衍生物，并利用RAW264.7细胞对其抗炎作用进行了评价。合成化合物的结构通过1h NMR，13C NMR和HRMS测定。所有化合物均通过抑制lps诱导的NO释放来筛选抗炎活性。其中，5-（3,4,5-三甲氧基苄基）-4-氧-4,5-二氢-[1,2,4]三唑[4,3-a]喹啉-1-羧酰胺（6p）抗炎活性最高，抑制NO释放的作用强于先导化合物dd1。进一步的研究表明，化合物6可产生NO、TNF-α和IL-6的水平，其抗炎作用涉及抑制COX-2和iNOS，下调丝裂原活化蛋白激酶（MAPK）信号通路。值得注意的是，化合物6在体内急性炎症模型中表现出比and1和阳性对照布洛芬更显著的抗炎活性。总之，这些发现表明化合物6p6是一种治疗炎症的候选药物。
To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using1H NMR,13C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compoundD1. Further studies revealed that compound6preduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound6pdisplayed more prominent anti-inflammatory activity thanD1and the positive control ibuprofen in thein vivoacute inflammatory model. Overall, these findings indicate that compound6pis a therapeutic candidate for the treatment of inflammation.