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 using 1H NMR, 13 C 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 compound D1. Further studies revealed that compound 6p reduced 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, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.

中文翻译：

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发现和评价新型合成的5-烷基-4-氧代-4,5-二氢-[1,2,4]三唑并[4,3-a]喹喔啉-1-甲酰胺衍生物作为抗炎剂。

为了开发新型抗炎药，设计，合成了一系列5-烷基-4-氧代-4,5-二氢-[1,2,4]三唑并[4,3-a]喹喔啉-1-甲酰胺衍生物。 ，并使用RAW264.7细胞评估其抗炎作用。使用1 H NMR，13 C NMR和HRMS确定合成的化合物的结构。根据所有化合物对LPS诱导的NO释放的抑制作用，筛选所有化合物的抗炎活性。其中，5-（3,4,5-三甲氧基苄基）-4-氧代-4,5-二氢-[1,2,4]三唑并[4,3-a]喹喔啉-1-甲酰胺（6p）显示最高的抗炎活性，并比先导化合物D1更有效地抑制NO的释放。进一步的研究表明，化合物6p可降低NO，TNF-α和IL-6的水平，并且其抗炎活性涉及抑制COX-2和iNOS以及下调丝裂原激活的蛋白激酶（MAPK）信号通路。值得注意的是，在体内急性炎症模型中，化合物6p显示出比D1和阳性对照布洛芬更突出的抗炎活性。总体而言，这些发现表明化合物6p是用于治疗炎症的治疗候选物。