Structural Modifications Of The Paeonol And Its Analogs And Their Stability In The Simulated Body Fluids And Anti-inflammatory Activities

Research objective:Combination principles mainly refer to the process of two kinds of bioactive compounds or more firstly connected via a covalent bond,secondly into the body and finally released active compounds through the effect of the degradation.The main purpose of combination is to produce better pharmacological activities,or to reduce the side effects,or to improve pharmacokinetic properties.The non-steroidal anti-inflammatory（NSAIDs）is extensively used in clinical application.However,the long-term administration of NSAIDs may cause many adverse reactions,especially the gastrointestinal side effects.Paeonol and its analogs along with NSAIDs all have anti-inflammatory activity.Paeonol and its analogs were combinated with naproxen,and the anti-inflammatory activity of the target compounds was greatly enhanced,But they are easy to hydrolyse in the body.In order to get strong anti-inflammatory activity and long half-life compounds,paeonol and its analogs were connected with1,4-dibromobutane,and then reacted with naproxen.Researchmethods:Paeonol,2-hydroxy-5-methoxyacetophenone,2-hydroxyacetophenone,3-hydroxyacetophenone,2,4-dihydroxyacetophenone were condensated with 1,4-dibromobutane,then reacted with naproxen yielding a series of target product.The structures of all synthesized compounds were characterized by IR,¹HNMR and MS.HPLC was used to examine the content of the target products,and their stability in simulated body fluid was observed under pH 1.2,5.0 and 7.4 buffer conditions at 37℃.The anti-inflammatory activities of target compounds were evaluated in xylene-induced mice ear swelling model and the content of PGE₂ in the inflammatory tissue.The side effects of the target compounds on the gastrointestinal tract of mice were investigated by the observation of electron microscope.Research results:Target compounds were characterized by IR,¹HNMR and MS.Usig HPLC can quickly and accurately determine the content of the compounds.The research of the stability of target compounds in simulated body fluid showed that these compounds have different stability in different pH buffer solution.Target compounds were stable at pH 1.2 and 5.0（they were more stable at pH 5.0）,but they were unstable under conditions of pH 7.4.Anti-inflammatory pharmacology studies showed that they exhibited more anti-inflammatory activity on the models of xylene-induced ear edema.Conclusion:The structure of the synthesized compounds is in accordance with the structure of the designed target compounds.The compounds are stable and easy to decompose.And they can resist the chemical degradation under acidic and alkaline conditions.The target compounds have significant anti-inflammatory activity compared with the control group（p<0.01）.The target compound reduced the content of PGE₂ in the inflammatory tissue.The anti-inflammatory mechanism may be related to the content of PGE₂ in inflammatory tissue.Gastrointestinal irritation test showed that the synthesized compounds could reduce the side effects of gastrointestinal tract in mice.