Design,Synthesis,and Biological Evaluation Of Paeonol Derivatives

Thromboembolic disease has become one of the major diseases that endanger human health,and its incidence rate is higher in all kinds of diseases.Abnormal increase in platelet aggregation rate is one of the major risk factors for thrombotic events.Clinical studies have shown that antiplatelet drugs can effectively reduce the incidence of cardiovascular and cerebrovascular diseases.However,due to its adverse effects in the clinic such as drug resistance and hemorrhage,it is necessary to further study and develope the antiplatelet aggregation agents with strong side effects and low side effects.Paeonol is one of the main active ingredients from the traditional Chinese medicine.It has many pharmacological activities,such as anticoagulation,antiplatelet aggregation,antibacterial,antitumor,antiviral,anti-inflammatory,antiallergic,antioxidation and prevention of heart and brain.However,due to the sublimation,poor water solubility and rapid metabolism rate in vivo,paeonol has been limited in its clinical application.Therefore,in order to enhance its activity and improve its deficiency,the structural modification of paeonol has a good prospect of research and development.In this paper,paeonol is used as the lead compound,the paeonol acetic acid intermediate were synthesize by carboxymethylated.Then the carboxyl group was coupled with the organic nitrate ester NO donor and the nitrogen-containing heterocyclic coupling.Two kinds of paeonol acetic acid derivatives were designed and synthesized.There are 5 target compounds of Class I and 25 target compounds of Class II.These target compounds were characterized by infrared spectroscopy,nuclear magnetic resonance spectroscopy and mass spectrometry.The anti-platelet aggregation activity of the target compounds was detected by turbidimetry.The results showed that the target compounds had stronger anti-platelet aggregation activity.Compounds II2,II7,II12 and II22 showed strong inhibition ofplatelet aggregation activity with IC50 of 0.530 mmol /L and 0.593 mmol/L,0.443 mmol /L and 0.445 mmol /L,respectively.Their anti-platelet aggregation activity was stronger than the positive control aspirin(IC50=0.890 mmo L/L).As a result,it is obivous that the target compounds(Class I)had a significant lipid-regulating effect by the bioactivity test in vivo,and its reduction of TC and TG was stronger than that of paeonol.The water-solubility tests were performed on target compounds(II2,II7-8,II12,II19,and II22)with strong antiplatelet aggregation activity.The results showed that the water solubility of the target compounds was greatly improved and the solubility reached to 272.03-420.02 mg/m L,which was 777 to 1200 times higher than the paeonol solubility(0.35 mg/m L).The preliminary structure-activity relationship analysis showed that the anti-platelet aggregation activity of class II target compounds mainly depended on their structure.It is noted that the different coupling structures and the length of the linker could affect their anti-platelet aggregation activity.Furthermore,when the carbon number of the linker is 3,the platelet aggregation activity is better.