Synthesis And Anti-inflamatory And Analgesic Activity Of Some4-hydroxy-2-benzoxazolone Acetic Acid Derivatives And Their Effectes On α-amylase Activity

Objective:To study the synthesis, anti-inflammatory and analgesic activity of the carboxylic acid derivatives of Ilicifolius alkaloids A (4-Hydroxy-2-benzoxazolone, HBOA) and their effectes on a-amylase and search for novel derivatives of Ilicifolius alkaloids A with better efficacy and explore their application areas.Methods:HBOA, obtained from2-nitroresorcinol with reduction and subsequent condensation with urea by "one-pot-way", reacted with ethanoyl chloride in DMF to yield4-Acetoxy-2-benzoxazolone(AcO-BOA).According to the medicine design principles,some carboxylic acid derivatives were designed.The compounds1-5were prepared with AcO-BOA and chloroacetic acid esters, and synthesized compounds6,7with HBOA and chloroacetic acid esters. HBOA reacted with chlorine Acetanilide to afford compounds8.The anti-inflammatory activities of the carboxylic acid derivatives were evaluated by the xylene-induced mice ear swelling model. The analgesic activities of the carboxylic acid derivatives were evaluated by the acetic acid induced stretching test and hot-plate method. The influence of the carboxylic acid derivatives upon the mice coagulation-time and bleeding-time were evaluated with the capillary method and measuring by cutting the tail of mice.the effects of derivatives of HBOA on a-amylase activity were compared by Bernfeld method.Results:Eight carboxylic acid derivatives of HBOA were synthesized, which structures were identified by IR,1H-NMR,13C-NMR and MS,and the wave information was matched with the title compounds.Compounds2,3and4exhibited significant anti-inflammatory activity in comparison with aspirin in xylene-induced mice ear swelling model and compounds8showed higher anti-inflammatory activity than Aspirin.Eight derivatives exhibited significant analgesic activities comparable to aspirin in HAc-induced stretching test, but none of them was observed analgesic activities in hot-plate test.Experiments of cutting tail method showed, compound1,3,4and5has a prolongation of bleeding time (BT) compared with aspirin. Capillary method showed that, compound2,4and5has a prolongation of coagulation-time (CT) compared with aspirin,and compound3has a greater extension than aspirin,whereas, compound8showed the Contrary trend.As shown in the influence of the derivatives upon α-amylase activity, a-1,a-2,a-3,a-4,a-5,b-6,c-8exhibited significant inhibition, in which a-2,a-3,a-5,b-6showed stronger activity.While a-7,b-14,b-3,c-3,c-4could reinforce the activity of a-amylase,and c-3,c-4showed higher activity than a-7,b-14and b-3.Conclusion:The synthetic processes of carboxylic acid derivatives of HBOA,prepared from HBOA or AcO-BOA with chloroacetic acid esters or chlorine Acetanilide,has the advantages of easy control and stable yield.All carboxylic acid derivatives have not been reported.Four derivatives(compound2,3,4,8) deserve further research, which possess good anti-inflammatory and analgesia activities.The influence of the derivatives upon the mice BT-CT,compound3,4and compound5showed great extension, while compound8showed signification short.In order to better define the inhibition effects of a-amylase there is a need to synthesize some HBOA derivatives which carry chlorine atom, acyl group or hydroxyl group at position7of the HBOA and retain the phenolic hydroxyl group at position4. However, taking acetoxyl group at position4and carboxyl group at position7or small group or carboxylic-acidyl at position3could reinforce the activity of a-amylase.