Dysregulation of neuroinflammation is a key pathological factor in the progressive neuronal damage of neurodegenerative diseases. An in-house natural products library of 1407 compounds were screened against neuroinflammation in lipopolysaccharide (LPS)-activated microglia cells to identify a novel hit 1,6-O,O-diacetylbritannilactone (OABL) with anti-neuroinflammatory activity. Furthermore, a 1,10-seco-eudesmane sesquiterpenoid library containing 33 compounds was constructed by semisynthesis of a major component 1-O-acetylbritannilactone (ABL) from the traditional Chinese medicinal herb Inula Britannica L. Compound 15 was identified as a promising anti-neuroinflammatory agent by nitrite oxide (NO) production screening. 15 could attenuate tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) productions, and inhibit the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at a submicromolar level. Mechanistic study revealed that 15 significantly modulated TLR4/NF-kB and p38 MAPK pathways, and upregulated the anti-oxidant response HO-1. Besides, 15 promoted the conversion of the microglia from M1 to M2 phenotype by increasing levels of arginase-1 and IL-10. The structure-activity relationships (SARs) analysis indicated that the α-methylene-γ-lactone motifs, epoxidation of C5=C10 bond and bromination of C14 were important to the activity. Parallel artificial membrane permeation assay (PAMPA) also demonstrated that 15 and OABL can overcome the blood-brain barrier (BBB). In all, compound 15 is a promising anti-neuroinflammatory lead with potent anti-inflammatory effects via the blockage of TLR4/NF-κB/MAPK pathways, favorable BBB penetration property, and low cytotoxicity.

神经炎症失调是神经退行性疾病进行性神经元损伤的关键病理因素。针对脂多糖 (LPS) 激活的小胶质细胞中的神经炎症对 1407 种化合物的内部天然产物库进行了筛选，以确定具有抗神经炎症活性的新型命中 1,6-O,O-二乙酰布列坦尼内酯 (OABL) 。此外，通过半合成中草药 Inula Britannica L 的主要成分 1-O-乙酰布列坦尼内酯 (ABL)，构建了一个包含 33 个化合物的 1,10-seco-eudesmane 倍半萜类化合物库。化合物 15 被确定为一种有前途的抗-通过亚硝酸盐（NO）产生筛选的神经炎症剂。15可以减弱肿瘤坏死因子-α（TNF-α）和前列腺素E2（PGE2）的产生，并在亚微摩尔水平抑制诱导型一氧化氮合酶（iNOS）和环氧合酶2（COX-2）的表达。机理研究表明，15 显着调节 TLR4/NF-kB 和 p38 MAPK 通路，并上调抗氧化反应 HO-1。此外，15 通过增加 arginase-1 和 IL-10 的水平促进了小胶质细胞从 M1 表型向 M2 表型的转变。构效关系(SARs)分析表明α-亚甲基-γ-内酯基序、C5=C10键的环氧化和C14的溴化对活性很重要。平行人工膜渗透试验 (PAMPA) 也证明 15 和 OABL 可以克服血脑屏障 (BBB)。总之，化合物 15 是一种很有前途的抗神经炎性铅通过阻断 TLR4/NF-κB/MAPK 通路具有有效的抗炎作用，具有良好的 BBB 渗透性和低细胞毒性。