Design,Synthesis,Activity Evaluation And Structure-Activity Relationship Of Novel Paeonol Derivatives

Paeonol has been proved to have potential anti-inflammatory efficacy,but its clinical application is not extensive compared to traditional non-steroidal anti-inflammatory drugs such as celecoxib,ibuprofen,indomethacin.Preliminary experimental studies show that anti-inflammatory activity of paeonol is poor（14.74%inhibitory activity at 20μM）.Based on the preliminary experimental results above,this project aims to improve the activity of paeonol,Series of derivatives were characterized by ¹H-NMR,¹³C-NMR and HR-MS.40 paeonol derivatives were designed and synthesized.Here,their anti-inflammatory activities were screened in vitro and in vivo.Structure-activity relationships 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 20μM and IC₅₀ value of 6.96μM against LPS-induced over expression of NO in RAW 264.7 macrophages.Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein,resulting in inhibiting cell signaling pathway of NF-κB and MAPK.Further studies have shown that compound 11a has obvious therapeutic effect in the rat arthritis model by adjuvant-induced.This research brings insight into the treatment of inflammatory diseases and title compound 11a may serve as a lead compound for the development of anti-AA agents.