本文選題：靛紅 + 合成�。� 參考：《浙江海洋學院》2014年碩士論文

【摘要】：靛紅（Isatin，ISA)，靛紅屬于一種新型天然的海洋藥物，是龍蝦、長臂蝦體內(nèi)賴以為生的活性物質(zhì)。靛紅存在于人和動物體內(nèi)，它屬于一種內(nèi)源性活性因子。其化學結(jié)構(gòu)明確，具有多種生物活性且毒性低，由其合成的一系列衍生物都具有較高的生物活性和應用價值，因而對于新藥研發(fā)具有十分重要的意義。為尋找到高療效且神經(jīng)毒副作用小的抗驚厥藥和抗抑郁藥，本文以Isatin為先導化合物，采用新藥設(shè)計的原理設(shè)計合成了一系列Isatin衍生物，此類衍生物合成以苯胺為起始原料，通過Sandmeyer合成法得到靛紅，再經(jīng)酰胺化反應，親核取代反應，制備了共32個Isatin衍生物，對所合成的目標化合物進行了抗驚厥活性研究，對Isatin衍生物（4a-q）進行了抗抑郁活性研究。 研究方法：常規(guī)合成方法得到了兩系列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），利用薄層色譜技術(shù)跟蹤檢測實驗，利用重結(jié)晶純化化合物，，使用熔點測試、波譜分析技術(shù)(IR,1H-NMR,13C-NMR, MS)和元素分析等技術(shù)進行結(jié)構(gòu)表征。采用最大電驚厥發(fā)作模型和戊四唑模型，評估其抗驚厥活性，采用旋轉(zhuǎn)法測試了其神經(jīng)毒性。利用強迫游泳實驗，對Isatin衍生物（4a-q）的抗抑郁活性進行了研究。 研究結(jié)果： （一）、對14個Isatin衍生物（3a-n）進行最大電驚厥模型研究：實驗結(jié)果表明，其中10個化合物具有抗最大電驚厥活性，先導化合物Isatin僅在給藥劑量300mg/kg濃度下呈現(xiàn)出抗最大電驚厥活性，9個Isatin衍生物（3a-3d,3f,3g,3i,3l和3n）在給藥劑量100mg/kg下表現(xiàn)出抗最大電驚厥活性，化合物3m在給藥劑量300mg/kg下具有抗最大電驚厥活性，但化合物(3e,3h,3j和3k)在給藥劑量300mg/kg下，不具有抗最大電驚厥活性。在旋轉(zhuǎn)法實驗中，相同劑量下并未表現(xiàn)出神經(jīng)毒性。對其中的抗最大電驚厥活性較好6個Isatin衍生物(3a-3d和3f,3i)的二期篩選，確定了構(gòu)效關(guān)系和神經(jīng)毒性：苯環(huán)上給電子基團抗抗最大電驚厥活性：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)，且其保護指數(shù)（PI=TD50/ED50,11）比上市藥苯巴比妥和卡馬西平都高。苯環(huán)上鹵素基團抗最大電驚厥活性：p-Fp-Clp-Br，其中化合物3f（p-F）具有最好的抗驚厥活性(ED50=88.0mg/kg,TD50800mg/kg),其保護指數(shù)(PI=TD50/ED50,9.1)高于上市藥苯巴比妥。 （二）、對18個Isatin衍生物（4a-q）進行了戊四唑小驚厥模型研究和強迫游泳實驗研究：戊四唑驚厥實驗實驗結(jié)果表明，在給藥劑量為100mg/kg下，所有化合物未表現(xiàn)出神經(jīng)毒性，其中12個化合物具有一定的抗驚厥活性，其中化合物4a，4f和4p活性最好，其測試結(jié)果和抗癲癇藥卡馬西平（100mg/kg）藥效一致；強迫游泳實驗結(jié)果表明，在給藥劑量100mg/kg濃度下，其中4個Isatin衍生物(I，4m，4p，4q)相對于空白組而言表現(xiàn)較好的抗抑郁活性。 主要結(jié)論：本文在先導化合物Isatin的基礎(chǔ)上，進行結(jié)構(gòu)修飾，合成了一系列的Isatin衍生物，對其抗驚厥活性和抗抑郁活性做了相關(guān)研究，初步評價了其抗驚厥活性和抗抑郁活性，對部分抗驚厥活性較好的化合物進行了二期篩選，探討了其構(gòu)效關(guān)系，為進一步開發(fā)新的高效低毒抗驚厥藥和抗抑郁藥提供了可能。
[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.
【學位授予單位】：浙江海洋學院
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：TQ463;R96

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