Study On The Synthesis And Anti-inflammatory And Analgesic Activitis Of The 2-substituted Derivatives Of Acetyl-benzoxazole-2-thione

Objective:The optimized synthesis conditions of 4-hydeoxy-benzo[d]oxazo--le-2(3H)--thione(HBOT)with response surface methodology(RSM).Libraries of 2-substituted derivatives of AcO-BOT were synthesized.The synthesized compounds have been tested for their anti-inflammatory activity and anti-nocic--eptive activity.Method:2-amimoresorcinol hydeochloride reacted with potassium ethyl xanthate(Potassium ethylxanthate)to synthesis HBOT.HBOT reacted with ethanoyl chloride in DMF to synthesis 4-Acetoxy-2-benzoxazole thione(AcO-BOT).According to drug design principle,Libraries of 2-substituted derivatives of AcO-BOT have been designed.The derivatives containing different benzyl chloride of AcO-BOT have been synthesized,namely C1,C2,C3,C4,C6,C7,C8,C9.The 2-substituted derivatives have been tested for their anti-inflammatory activities by using the dimethyl-benzene-induced mice ear swelling model.The 2-substituted derivatives have been tested for their anti-nociceptive activity by the acetic acid induced stretching test and hot-plate method.The 2-substituted derivatives have been tested for the side effects by the mice coagulation-time and bleeding-time.Results:Eight derivatives were synthesized,which structures were identified by IR,1H-NMR,13C-NMR and MS,and the wave information was matched with the title compounds.Compound HBOT,Aco-BOT,C4,C7,C8,C9 showed significant anti--inflammatory activity in comparison with aspirin in dimethylbenzene-induced mice ear swelling model.Compound HBOT,Aco-BOT,C1,C2,C4 showed significant anti-nocicep--tive activity in comparison with aspirin in HAc-induced writhing test.Compounds HBOT,Aco-BOT,C1,C2,C3,C4,C6,C7 possessed significant anti-inflammatory activity as compared to the standard drug aspirin.Experiments of cutting tail method showed,none of 2-substituted derivatives had a prolongation of bleeding time(BT)in comparison with aspirin.Capillary method showed that,compound Aco-BOT,C3,C6,C8,C9 have a prolongation of coagulation-time(CT)in comparison with aspirin,whereas,compound HBOT,C1,C4 showed the contrary trend.Conclusion:1.The optimized method of synthesis of HBOT with response surface methodology(RSM)had a high and stable yield.The synthesis of 2-substituted derivatives of HBOT,which were prepared from AcO-BOT with corresponding benzyl chloride,had the advantages of easy control and stable yield.2.All 2-substituted derivatives have not been reported.3.Six derivatives(compound HBOT,Aco-BOT,C1,C2,C4,C6)deserve further research,which possess good anti-inflammatory and anti-nociceptive activities.