Isatin衍生物的合成及其抗惊厥、抗抑郁活性研究

发布时间：2018-05-18 15:28

本文选题：靛红 + 合成　；参考：《浙江海洋学院》2014年硕士论文

【摘要】：靛红（Isatin，ISA)，靛红属于一种新型天然的海洋药物，是龙虾、长臂虾体内赖以为生的活性物质。靛红存在于人和动物体内，它属于一种内源性活性因子。其化学结构明确，具有多种生物活性且毒性低，由其合成的一系列衍生物都具有较高的生物活性和应用价值，因而对于新药研发具有十分重要的意义。为寻找到高疗效且神经毒副作用小的抗惊厥药和抗抑郁药，本文以Isatin为先导化合物，采用新药设计的原理设计合成了一系列Isatin衍生物，此类衍生物合成以苯胺为起始原料，通过Sandmeyer合成法得到靛红，再经酰胺化反应，亲核取代反应，制备了共32个Isatin衍生物，对所合成的目标化合物进行了抗惊厥活性研究，对Isatin衍生物（4a-q）进行了抗抑郁活性研究。研究方法：常规合成方法得到了两系列Isatin衍生物，即2，3-二氧代吲哚啉-1-N-苯基乙酰胺系列（3a-n）和5-甲基-2，3-二氧代吲哚啉乙酰胺系列（4a-q），利用薄层色谱技术跟踪检测实验，利用重结晶纯化化合物，，使用熔点测试、波谱分析技术(IR,1H-NMR,13C-NMR, MS)和元素分析等技术进行结构表征。采用最大电惊厥发作模型和戊四唑模型，评估其抗惊厥活性，采用旋转法测试了其神经毒性。利用强迫游泳实验，对Isatin衍生物（4a-q）的抗抑郁活性进行了研究。研究结果：（一）、对14个Isatin衍生物（3a-n）进行最大电惊厥模型研究：实验结果表明，其中10个化合物具有抗最大电惊厥活性，先导化合物Isatin仅在给药剂量300mg/kg浓度下呈现出抗最大电惊厥活性，9个Isatin衍生物（3a-3d,3f,3g,3i,3l和3n）在给药剂量100mg/kg下表现出抗最大电惊厥活性，化合物3m在给药剂量300mg/kg下具有抗最大电惊厥活性，但化合物(3e,3h,3j和3k)在给药剂量300mg/kg下，不具有抗最大电惊厥活性。在旋转法实验中，相同剂量下并未表现出神经毒性。对其中的抗最大电惊厥活性较好6个Isatin衍生物(3a-3d和3f,3i)的二期筛选，确定了构效关系和神经毒性：苯环上给电子基团抗抗最大电惊厥活性：p-CH3-Ho-CH3m-CH3，其中化合物3d（p-CH3）具有最好的活性（ED50=91.3mg/kg，TD501000mg/kg)，且其保护指数（PI=TD50/ED50,11）比上市药苯巴比妥和卡马西平都高。苯环上卤素基团抗最大电惊厥活性：p-Fp-Clp-Br，其中化合物3f（p-F）具有最好的抗惊厥活性(ED50=88.0mg/kg,TD50800mg/kg),其保护指数(PI=TD50/ED50,9.1)高于上市药苯巴比妥。（二）、对18个Isatin衍生物（4a-q）进行了戊四唑小惊厥模型研究和强迫游泳实验研究：戊四唑惊厥实验实验结果表明，在给药剂量为100mg/kg下，所有化合物未表现出神经毒性，其中12个化合物具有一定的抗惊厥活性，其中化合物4a，4f和4p活性最好，其测试结果和抗癫痫药卡马西平（100mg/kg）药效一致；强迫游泳实验结果表明，在给药剂量100mg/kg浓度下，其中4个Isatin衍生物(I，4m，4p，4q)相对于空白组而言表现较好的抗抑郁活性。主要结论：本文在先导化合物Isatin的基础上，进行结构修饰，合成了一系列的Isatin衍生物，对其抗惊厥活性和抗抑郁活性做了相关研究，初步评价了其抗惊厥活性和抗抑郁活性，对部分抗惊厥活性较好的化合物进行了二期筛选，探讨了其构效关系，为进一步开发新的高效低毒抗惊厥药和抗抑郁药提供了可能。
[Abstract]:Dian Hong (Isatin, ISA), Dian Hong belongs to a new natural marine drug, the active substance that is the living substance of lobster and lobster. Dian Hong exists in human and animal body, it belongs to an endogenous active factor. Its chemical structure is clear, with a variety of bioactivity and low toxicity, a series of derivatives which are synthesized by it have high level. In order to find the anticonvulsant and antidepressant drugs with high curative effect and small side effects of neurotoxicity, a series of Isatin derivatives are designed and synthesized with the principle of new drug design by using Isatin as the precursor compound. Indigo was obtained by Sandmeyer synthesis, and then 32 Isatin derivatives were prepared by acylation reaction and nucleophilic substitution reaction. The anticonvulsant activity of the synthesized target compounds was studied and the antidepressant activity of Isatin derivatives (4a-q) was studied.
Research methods: two series of Isatin derivatives, namely, 2,3- two oxindoline -1-N- phenyl acetamide series (3a-n) and 5- methyl -2,3- two oxindoline ethyl amide series (4a-q), are obtained by TLC technology tracking test, using recrystallized pure compounds, using melting point testing, spectrum analysis (1H-N). MR, 13C-NMR, MS) and elemental analysis were used for structural characterization. The anticonvulsant activity was evaluated with the maximum electrical convulsion model and pentylenetezol model, and its neurotoxicity was tested by rotating method. The antidepressant activity of Isatin derivative (4a-q) was studied by forced swimming test.
The results of the study:
(1) the maximum electrical convulsion model of 14 Isatin derivatives (3a-n) was studied. The experimental results showed that 10 of them had the maximum electrical convulsion activity. The pilot compound Isatin showed the maximum electrical convulsion activity only under the dose of 300mg/kg, and the 9 Isatin derivatives (3A-3D, 3F, 3G, 3I, 3L and 3n) were in the dosage 100mg/kg The maximum electrical convulsion activity was shown to resist the maximum electrical convulsion activity, and the compound 3M had the maximum electrical convulsion activity under the dose of 300mg/kg, but the compound (3E, 3h, 3j and 3K) did not have the maximum electrical convulsion activity under the dose of dose 300mg/kg. In the rotation experiment, the neurotoxicity was not shown at the same dose. The anti convulsion activity of the compound was more than that of the same dose. The two phase screening of 6 Isatin derivatives (3A-3D and 3F, 3I) determined the structure-activity relationship and neurotoxicity: the maximum electrical convulsion activity of the electron group on the benzene ring: p-CH3-Ho-CH3m-CH3, in which the compound 3D (p-CH3) has the best activity (ED50=91.3mg/kg, TD501000mg/ kg), and its protective index (PI=TD50/ED50,11) is compared to the phenobarbital of the listed drug. The maximum electrical convulsion activity of the halogen group on the benzene ring is p-Fp-Clp-Br, p-Fp-Clp-Br, in which compound 3f (p-F) has the best anticonvulsant activity (ED50=88.0mg/kg, TD50800mg/kg), and its protective index (PI=TD50/ED50,9.1) is higher than that of phenobarbital on the market.
(two) 18 Isatin derivatives (4a-q) were studied by pentylenetezol small convulsion model and forced swimming test. The results of pentylenetezol convulsion experiment showed that all compounds did not exhibit neurotoxicity under the dosage of 100mg/kg, of which 12 compounds had certain anticonvulsant activity, of which compounds 4a, 4f and 4P were most active. Well, the results of the test were consistent with the antiepileptic drug carbamazepine (100mg/kg), and the results of forced swimming test showed that 4 of the Isatin derivatives (I, 4m, 4P, 4q) showed better antidepressant activity compared with the blank group at the concentration of 100mg/kg.
Main conclusions: on the basis of the pilot compound Isatin, a series of Isatin derivatives were synthesized, and their anticonvulsant and antidepressant activities were studied. The anticonvulsant activity and antidepressant activity were preliminarily evaluated. Two stages of screening for some compounds with better anticonvulsant activity were investigated. Its structure-activity relationship provides the possibility for further development of new highly effective and low toxic anticonvulsants and antidepressants.
【学位授予单位】：浙江海洋学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：TQ463;R96

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