Synthesis And Activity Of The Novel Anti-inflammatory Drugs Based On Paeonol And Its Structural Analogues

Ibuprofen 、 Naproxen and Ketoprofen are typical drugs of aryl propionic acid non-steroidal anti-inflammatory drugs(NSAIDs),with anti-inflammatory,antipyretic,analgesic properties.However,some researches have indicated that long-term oral administration of NSAIDs may cause gastrointestinal adverse reactions,mainly gastrointestinal ulcer,gastrointestinal bleeding and gastric perforation.To synthesize pro-drug through carboxyl group of NSAIDs is one of effective ways to reduce gastrointestinal toxic and side effects.Paeonol and its structural analogs are a kind of small molecule phenolic compounds.In recent years,pharmacological experimental studies have shown that they have a wide range of biological activities,including anti-inflammation,analgesia and antibacterial activity et al.However,Paeonol is easily be oxidized when contacting air for a long time due to its phenolic hydroxyl group.It is difficult to preserve for a long term.In this paper,the NSAIDs(ibuprofen,naproxen and ketoprofen)and Paeonl analogs(Paeonol and 2-hydroxy-5-methoxy-acetophenone,3-hydroxyacetophenone,2-hydroxyacetophenone and 3-methoxy-phenol)which have similar pharmacological activity were made into prodrug by combination principle.We expect that the new prodrugs can enhance their antipyretic,analgesic and anti-inflammatory acticity,and reduce or mitigate NSAIDs gastrointestinal adverse reactions.Paeonol and its structural analogues which have anti-oxygen free radical action can reduce the generation of stomach ulcer,increase the fat solubie,reduce residence time of prodrug in the gastrointestinal tract.Research methods: Fifteen compounds were synthesized by Paeonol or its analogues condensing with ibuprofen,naproxen and ketoprofen by acyl chloride method or DCC method.namely: ibuprofen derivatives(P1~P5),naproxen derivative(Q1~Q5)and ketoprofen derivatives(R1~R5).It has been reported for P1,Q1 and R1.The structures of all synthesized compounds were characterized by IR,1HNMR and MS.Established adetermination of the content by HPLC and studied their degradation dynamics properties under p H 1.2,5.0 and 7.4 buffer conditions at the temperature of 37 ℃.Anti-inflammatory activities of the compounds were evaluated in xylene-induced mice ear swelling model.Research resu Lts: Target compounds were characterized by IR,1HNMR and MS.The method of HPLC which was established can quickly and accurately determine the content of the compounds.Degradation Kinetic experiments showed that these compounds have different stability at different p H buffer solution.Target compounds were stable at p H 1.2 and 5.0(they were more stable at p H 5.0),relatively poor stability under conditions of p H 7.4.Anti-inflammatory pharmacology studies shown that they exhibited potent activities on the models of xylene-induced ear edema.Conc Lusion: The synthesis of the compounds conforms to the structure of the target compounds envisaged.Target compounds were not easily broken in simulated gastrointestinal fluid stability,can resist chemical degradation in the condition of acidic and alkaline.Target compounds have significant anti-inflammatory activity compared with the control group(P <0.01).