Mohan Sangeetha, Krishnan Lekshmy, Madhusoodanan Nithya, Sobha Anjali, Babysulochana Alansheeja D, Vankadari Naveen, Purushothaman Jayamurthy, Somappa Sasidhar B
Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram 695 019, Kerala India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India.
ACS Med Chem Lett. 2024 Jul 23;15(8):1260-1268. doi: 10.1021/acsmedchemlett.4c00141. eCollection 2024 Aug 8.
This study employed a ligand-based pharmacophoric approach to design and synthesize 33 novel semisynthetic labdane-appended triazolyl isatins to discover potential anti-inflammatory agents. The anti-inflammatory efficacy of the derivatives was evaluated by their ability to inhibit the production of NO, TNF-α, and IL-6, in lipopolysaccharide-induced RAW264.7 macrophages. The initial screening revealed that compound ((1-(2-(2,3-dioxoindolin-1-yl)ethyl)-1-1,2,3-triazol-4-yl)methyl ()-3-formyl-5-((1,4a,8a)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)pent-3-enoate) exhibited an anti-inflammatory effect (NO inhibition, IC = 3.13 μΜ), surpassing both the positive control indomethacin (NO inhibition, IC = 7.31 μΜ) and the parent compound labdane dialdehyde. Notably, reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the levels of the anti-inflammatory cytokine IL-10. Mechanistic studies revealed that downregulated the expression of COX-2 and iNOS by inhibiting the NF-κB signaling pathway. In silico molecular modeling studies on NF-κB proteins support these findings, suggesting that is a promising candidate for developing into a potent anti-inflammatory clinical agent.
本研究采用基于配体的药效团方法设计并合成了33种新型半合成的附加半日花烷的三唑基异吲哚酮，以发现潜在的抗炎剂。通过评估这些衍生物在脂多糖诱导的RAW264.7巨噬细胞中抑制一氧化氮（NO）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）产生的能力，来评价其抗炎效果。初步筛选显示，化合物（（1-(2-(2,3-二氧代吲哚啉-1-基)乙基)-1H-1,2,3-三唑-4-基）甲基（）-3-甲酰基-5-((1,4a,8a)-5,5,8a-三甲基-2-亚甲基十氢萘-1-基)戊-3-烯酸酯）表现出抗炎作用（NO抑制，IC50 = 3.13 μΜ），超过了阳性对照吲哚美辛（NO抑制，IC50 = 7.31 μΜ）和母体化合物半日花烷二醛。值得注意的是，该化合物降低了促炎细胞因子TNF-α和IL-6的水平，同时提高了抗炎细胞因子IL-10的水平。机制研究表明，该化合物通过抑制核因子-κB（NF-κB）信号通路下调了环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的表达。对NF-κB蛋白的计算机辅助分子模拟研究支持了这些发现，表明该化合物有望开发成为一种有效的抗炎临床药物。
