School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, China.
Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
Chem Biol Drug Des. 2021 Feb;97(2):200-209. doi: 10.1111/cbdd.13784. Epub 2020 Sep 22.
In an effort to discover new agents with high anti-inflammatory activity, 22 new 4-sulfonyloxy/alkoxy benzoxazolone derivatives were synthesized, characterized, and evaluated for their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and TNF-α expression in RAW 264.7 cells in vitro. Most of these compounds displayed greater inhibitory ability against NO production than the lead compound 4-o-methyl-benzenesulfonyl benzoxazolone, and the most active compound 2h exhibited the strongest inhibitory activity against NO, IL-1β, and IL-6 production with IC values 17.67, 20.07, and 8.61 μΜ, respectively. The effects of 2h were comparable or stronger than those of the positive control celecoxib. Compound 2h also displayed higher activity in vivo than celecoxib in a mouse model of xylene-induced ear edema, based on their inhibitory rates of 42.69% and 30.87%, respectively. Further molecular analysis revealed that compound 2h significantly reduced the iNOS levels in cell supernatant and suppressed the protein expression of iNOS, p-p38, p-ERK, and nuclear NF-κB. The results indicated that the anti-inflammatory effect of 2h might be realized through the regulation of ERK- and p38-mediated mitogen-activated protein kinase (MAPK)-NF-κB/iNOS signaling, thereby reducing the excessive release of NO, IL-1β, and IL-6. Our findings demonstrated that compound 2h, a new benzoxazolone derivative, could inhibit activation of the MAPK-NF-κB/iNOS pathway, supporting its potential as a novel anti-inflammatory agent.
为了发现具有高抗炎活性的新化合物，我们合成了 22 种新的 4-磺酰氧基/烷氧基苯并恶唑酮衍生物，并对其进行了表征，评估了它们在体外对脂多糖（LPS）诱导的 RAW 264.7 细胞中一氧化氮（NO）产生和 TNF-α表达的抗炎活性。这些化合物中的大多数对 NO 产生的抑制能力大于先导化合物 4-o-甲基苯磺酰基苯并恶唑酮，最活性化合物 2h 对 NO、IL-1β 和 IL-6 的抑制活性最强，IC 值分别为 17.67、20.07 和 8.61 μM。2h 的作用与阳性对照塞来昔布相当或更强。基于 2h 在二甲苯诱导的耳肿胀小鼠模型中的抑制率分别为 42.69%和 30.87%，2h 在体内的活性也比塞来昔布更强。进一步的分子分析表明，化合物 2h 显著降低了细胞上清液中 iNOS 的水平，并抑制了 iNOS、p-p38、p-ERK 和核 NF-κB 的蛋白表达。结果表明，2h 的抗炎作用可能通过调节 ERK 和 p38 介导的丝裂原激活蛋白激酶（MAPK）-NF-κB/iNOS 信号通路来实现，从而减少 NO、IL-1β 和 IL-6 的过度释放。我们的研究结果表明，作为一种新的苯并恶唑酮衍生物，化合物 2h 可以抑制 MAPK-NF-κB/iNOS 通路的激活，支持其作为一种新型抗炎剂的潜力。
