School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
School of Pharmacy, Anhui Medical University, Hefei 230032, PR China.
Bioorg Chem. 2020 May;98:103735. doi: 10.1016/j.bioorg.2020.103735. Epub 2020 Mar 8.
Paeonol has been proved to have potential anti-inflammatory activity, but its clinical application is not extensive due to the poor anti-inflammatory activity (14.74% inhibitory activity at 20 μM). In order to discover novel lead compound with high anti-inflammatory activity, series of paeonol derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. Structure-activity relationships (SARs) have been fully concluded, and finally (E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3,4,5-trimet-hoxyphenyl)acrylamide (compound 11a) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 μM and IC value of 6.96 μM against LPS-induced over expression of nitric oxide (NO) in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4, resulting in inhibiting of NF-κB and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.
丹皮酚已被证明具有潜在的抗炎活性，但由于抗炎活性差（20 μM 时抑制活性为 14.74%），其临床应用并不广泛。为了发现具有高抗炎活性的新型先导化合物，设计并合成了一系列丹皮酚衍生物，对其进行了体外和体内抗炎活性筛选。充分总结了构效关系（SARs），最终发现（E）-N-（4-（2-乙酰基-5-甲氧基苯氧基）苯基）-3-（3,4,5-三甲氧基苯基）丙烯酰胺（化合物 11a）是毒性最低、活性最好的化合物，在 20 μM 时对 LPS 诱导的 RAW 264.7 巨噬细胞中一氧化氮（NO）过表达的抑制率为 96.32%，IC 值为 6.96 μM。初步机制研究表明，它可以抑制 TLR4 的表达，从而抑制 NF-κB 和 MAPK 通路。进一步的研究表明，化合物 11a 对佐剂诱导的大鼠关节炎模型有明显的治疗作用。
