3-芳基-1H-5-取代吡唑酰腙类化合物的合成与生物活性初探

Synthesis of 3-Aryl-1H-Pyrazole-5-Acylhydrazones and Their Biological Activities

目的合成一系列3-芳基-1H-5-取代吡唑酰腙类化合物,用于抗癫痫和抗炎活性筛选.方法以苯乙酮(或取代苯乙酮)为起始原料与草酸二乙酯发生缩合反应,然后与水合肼环化、肼解,最后与芳香醛(酮)缩合得到目标化合物5a-5o。采用最大电惊厥实验(MES)和皮下戊四唑实验(scPTZ)筛选其抗癫痫活性,旋转棒法评价其神经毒性;采用脂多糖(LPS)诱导TNF-α释放模型评价化合物的体外抗炎活性。结果部分化合物显示出抗最大电惊厥活性,大多数化合物显示出抗戊四唑诱导惊厥的活性。化合物5f在30 mg/kg下仍表现良好的抗戊四唑所致惊厥活性。所有化合物在300 mg/kg剂量下均未表现出神经毒性。大部分化合物在20μg/mL剂量下可以显著抑制LPS诱导的TNF-α浓度的升高,其中化合物5b,5h和5k的抑制率高于50%,与阳性药地塞米松相当。结论本研究报道的3-芳基-1H-5-取代吡唑酰腙类化合物具有较好的抗癫痫活性,尤其对戊四唑诱导癫痫更为敏感。此外,该系列化合物在细胞炎症模型中的表现出良好的体外抗炎活性。该研究为研究失神发作类癫痫和炎症的治疗药物提供了一定依据。

Objective:To synthesis a series of 3-aryl-1H-pyrazole-5-acylhydrazones and investigate their biological effects.Methods:The target compounds 5a-5o were synthesized by condensation of acetophenone(or substituted acetophenone)with diethyl oxalate,cyclization and hydrazinolysis with hydrazine hydrate,and condensation with aromatic aldehydes(ketones)successively.Their anticonvulsant activities were screened using maximal electroshock shock(MES)and subcutaneous pentylenetetrazole(scPTZ)seizure models in mice.Their neurotoxicity was evaluated with rotarod test.In vitro LPS-induced TNF-αmodel was used to evaluate their anti-inflammatory activity.Results:Their anticonvulsant activities,especially the anti-PTZ activity were confirmed by the both models.Most of them markedly inhibited the expression of TNF-αat the concentration of 20μg/mL.Compounds 5b,5h,and 5k were comparable to dexamethasone with a TNF-αinhibitory rate of more that 50%.Conclusion:The 3-aryl-1 H-pyrazole-5-acylhydrazones reported in this work exhibited anticonvulsant and anti-inflammatory activities.This found provides a certain basis to the research and development of new drugs of the absence seizure and inflammation.