Background: Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants. Methods: New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test. Results: Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)one О-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg. Conclusion: Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.

中文翻译：

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3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1-(2H)-酮肟肉桂酰基衍生物的设计、合成及抗惊厥活性


背景：癫痫仍然是一个重大的全球健康问题，寻找新的治疗药物仍然是一项紧迫的任务。 5-HT2 和 GABAA 受体是寻找新型抗惊厥药物的有前景的生物靶标。方法：利用药效团设计3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1-(2H)-酮肟系列取代肉桂酰基衍生物中新的潜在5-HT2和GABAA配体模型和分子对接分析。以3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1(2H)-酮肟和取代肉桂酰氯为原料合成新化合物。新物质的抗惊厥活性已通过最大电击癫痫发作试验确定。结果：几种合成的3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1-(2H)-酮肟的取代肉桂酰衍生物显着减轻了惊厥症状的严重程度并完全防止了动物的死亡MES之后。研究了结构-活性关系。最有效的化合物是 GIZH-348 (1g) (3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1-(2H)酮 О-(4-氯苯基)丙烯酰基)肟），剂量为 10-20 mg/kg。结论：分子和药效团建模方法使我们能够创建一组新的具有抗惊厥活性的 3,4,6,7,8,9-六氢二苯并[b,d]呋喃-1-(2H)-酮肟的取代肉桂酰衍生物。