三嗪酮衍生物的合成及抗癫痫作用研究

Epileptic has become a serious threat to human health because of higher accidental mortality. However, the effects of existing AEDs have not been satisfactory, it is of great significance to research and develop new AEDs. We have completed many National Natural Science Foundation projects and synthesized about more than 2000 triazoloquinoline derivatives. The structure-activity relationships of triazoloquinoline derivatives were also discussed. In our previous study, we found that the lead compounds benzooxazinotriazine showed stronger anticonvulsant activity and lower neurotoxicity. In this study, eight types of target compounds, which including aromatic ring, electron donor or receptors and amide linkage, were designed based on pharmacophore model of antiepileptic drugs, and by using bioisosterism and ring expansion. The obtained compounds were submitted for in vivo evaluation using the methods described in the Antiepileptic Drug Development Program (ADD) of the National Institutes of Health according to previously described testing procedures (USA). We use the maximal electroshock seizure test (MES) and the rotarod test to evaluate the anticonvulsant activity (ED50) and neurotoxicity of these compounds (TD50), respectively. In addition, some compounds were tested against convulsions induced by chemical substances (pentylenetetrazole, bicuculline, picrotoxin, 3-mercaptopropionic acid and isoniazide) with the aim to further investigate their anticonvulsant activity. Finally, to clarify their mechanism of action and to lay the foundation of finding the candidate compounds with development value for the treatment of epilepsy.

癫痫发作时意外死亡率较高，是严重危害人类健康的疾病。现有的抗癫痫药物效果不令人满意，因此研究与开发新抗癫痫药具有重要意义。通过完成多项国家自然基金项目，合成了2000多个喹啉并三唑类化合物，阐明了构效关系。从中发现了苯并氧嗪并三嗪类先导化合物，不仅具有较强的抗惊厥作用，同时具有较低的神经毒性。本项目目标物的设计利用了抗癫痫药的药效团模型，均具有芳环、电子供体或受体和酰胺键。同时利用了生物电子等排体、扩环等新药设计原理，设计出8种类型目标物。抗癫痫药理实验采用美国国立卫生院推荐的“抗癫痫药开发程序”，以最大电惊厥实验方法测定小鼠抗惊厥作用ED50，以旋转棒法测定神经毒性TD50。对抗惊厥作用强而神经毒性低的化合物，再进行抗戊四唑、荷包牡丹碱、印防己毒素、3-巯基丙酸、异烟肼等化学物质诱发惊厥实验，进一步证明其有效性。最后再阐明其作用机制，为寻找到有开发价值的候选抗癫痫化合物奠定基础。

本课题首先设计与合成设计了5-取代 -[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮类等衍生物，以最大电惊厥法测定了抗惊厥活性。这个实验结果证明，三唑环是重要的药效基团。设计合成了共计200多个衍生物。所合成的化合物的结构以IR、NMR、MS等方法确证。所有目标物以最大电惊厥法测定了抗惊厥活性，探讨了化学结构与活性的关系。从中发现了抗惊厥活性较的化合物，以旋转棒法测定了神经毒性。部分化合物还以戊四唑、异烟肼、3-巯基丙酸、硫代氨基脲等化学物质诱发的抗惊厥实验，初步阐明了作用机制，并进一步证明其有效性。对活性较好的具有开发价值的化合物申请了中国发明专利。本课题共发表SCI收录的论文20篇，申请专利3项。通过完成本课题，有12名获得硕士学位，4名获得博士学位。