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目的设计合成新型缩氨基脲类化合物,探讨结构中同时含有海因和缩氨基脲片段时其抗癫痫和抗肿瘤活性。方法依据拼合原理,将具有抗癫痫活性的环丙烷海因结构与缩氨基脲类结构结合起来并据此合成系列衍生物;采取通用的抗癫痫药物筛选模型[最大电惊厥实验(MES)、皮下注射戊四唑实验(sc PTZ)和神经毒性实验(Neurotoxocity)]进行抗癫痫活性评价;应用MTT法测试目标物对不同细胞株的潜在抗肿瘤细胞活性。结果与结论合成了19个目标化合物,其中Ⅰa~Ⅰl及Ⅱa~Ⅱh未见文献报道;在抗癫痫测试中,化合物Ⅱa~Ⅱd在100 mg·kg-1剂量下抗惊厥效果明显,Ⅱb、Ⅱc及Ⅱd在300 mg·kg-1时有拮抗戊四氮的作用;除了Ⅲ、Ⅵ、Ⅰi、Ⅰj外的化合物均有严重的神经毒性;化合物Ⅱd对He La细胞系抑制最好,其IC50值为23.7μmol·L~(-1),化合物Ⅰd对Hep G2细胞系的IC50值为26.7μmol·L~(-1)。
OBJECTIVE To design and synthesize a new type of semicarbazone compound and to investigate its antiepileptic and antitumor activity when it contains both hydantoin and semicarbazone fragments. Methods Based on the principle of combination, cyclopropane hydantoin with antiepileptic activity and semicarbazone structure were combined to synthesize a series of derivatives. A generic antiepileptic drug screening model (MES, subcutaneous Injection of pentylenetetrazole (sc PTZ) and neurotoxocity (Neurotoxocity)] for evaluation of antiepileptic activity. The potential antitumor activity of the target against different cell lines was tested by MTT assay. RESULTS AND CONCLUSIONS Nineteen target compounds were synthesized, of which Ⅰa ~ Ⅰl and Ⅱa ~ Ⅱh were not reported in the literature. In the antiepileptic test, the compounds Ⅱa ~ Ⅱd had obvious anticonvulsant effect at doses of 100 mg · kg-1, Ⅱb and Ⅱc And Ⅱd antagonized pentylenetetrazole at 300 mg · kg-1. The compounds except Ⅲ, Ⅵ, Ⅰi and Ij all had serious neurotoxicity. The inhibitory effect of compound Ⅱd on He La cell line was the best, and the IC50 value Was 23.7μmol·L -1. The IC50 value of compound Ⅰd to Hep G2 cell line was 26.7μmol·L -1.