双酯基取代的1,5-苯并二氮杂卓类化合物的合成、抑菌活性及构效关系
发布时间：2019-02-16 03:50
【摘要】：1,5-苯并二氮杂卓类化合物是一类含有七元氮杂环的生物活性分子,具有独特的生理活性及药理活性。研究表明其具有抗惊厥、抗抑郁、治疗失眠、抗焦虑、和镇定等作用。近年来,多有研究报道1,5-苯并二氮杂卓还具有抑制细菌与真菌等作用。因此,1,5-苯并二氮杂卓类化合物的合成及抑菌活性的研究是药物合成研究的热点之一。本课题组一直致力于1,5-苯并二氮杂卓类化合物的合成及抑菌活性的研究。合成了多种新型1,5-苯并二氮杂卓类化合物,研究发现部分化合物在七元杂环上引入酯基具有很好的抑菌活性,即酯基是一种抑菌活性基团。本课题组前期研究结果表明:3-COOR取代的1,5-苯并二氮杂卓具有很好的抑菌活性和生物广谱性,因此本文设计合成了2,3位双酯基及4位长链酯基取代的新型1,5-苯并二氮杂卓类化合物,以期得到具有较高抑菌活性的化合物。本文还对上述化合物的构效关系进行了较为系统的研究。本论文的主要研究内容具体如下:1、C-4位上长链酯基结构的2-取代芳基-4-丙酸乙酯基-1,5-苯并二氮杂卓衍生物的合成:以乙酰丙酸乙酯、对位取代的苯甲醛、取代的邻苯二胺为原料,经羟醛缩合,亲核加成,脱水,环合等反应合成了7种未见文献报道的亚胺结构的2-取代芳基-4-丙酸乙酯基-1,5-苯并二氮杂卓衍生物。所有化合物的结构经核磁氢谱、碳谱、红外、质谱、元素分析表征,确定该类化合物的结构正确。2、双酯基结构的2,3-二酯基-4-烷基-1,5-苯并二氮杂卓的合成及抑菌活性研究:本文以邻苯二胺或取代的邻苯二胺、二羰基酯化合物、乙醛酸乙酯为原料,通过一锅两步串联反应合成了30种含有2,3位双酯基取代的1,5-苯并二氮杂卓类化合物。所有得到的化合物经核磁氢谱、核磁碳谱、红外光谱、质谱、元素分析等表征手段确定结构正确,并提出了可能的反应机理。采用滤纸片法将合成的30种2,3-二酯基-4-烷基-1,5-苯并二氮杂卓进行了体外抑菌测试,研究表明所有化合物均具有抑菌活性,其中24种化合物具有较高的抑菌活性,尤其是化合物IVu对标准新生隐球菌的抑菌圈直径可达29.27mm。将化合物IVu对标准新生隐球菌和新生隐球菌临床珠进行了MIC测试并与标准药物氟康唑对比,发现其MIC值大于标准药物氟康唑,可作为抑真菌先导化合物,用于药物开发。3、从结构与抑菌活性关系分析了化合物的多种取代基团与抑菌活性之间的构效关系;采用Gaussian 03量子化学程序包中密度泛函理论DFT计算方法,在B3LYP/6-31G基组水平上对部分所合成的含有双酯基的2,3-二酯基-4-烷基-1,5-苯并二氮杂卓类化合物进行了量化计算,从定量角度分析了相关理论参数与抑菌活性的关系,建立了定量构效关系一元方程,并对此进行了验证。该构效关系建立可为预测、发现活性更高的化合物提供理论依据。
[Abstract]:1 ~ (5)-benzodiazepines are a class of bioactive molecules containing seven-component nitrogen heterocycles, which have unique physiological and pharmacological activities. It has been shown to have anticonvulsant, antidepressant, insomnia, antianxiety, and calming effects. In recent years, it has been reported that 1o-5-benzodiazepines can also inhibit bacteria and fungi. Therefore, the synthesis and antimicrobial activity of 1C-5-benzodiazepines are one of the hotspots in drug synthesis. Our research group has been devoted to the synthesis and antibacterial activity of 1 ~ 5-benzodiazepines. A variety of novel 1 & 5-benzodiazepines were synthesized. It was found that some of the compounds introduced ester groups into seven heterocyclic compounds had good bacteriostatic activity, that is, ester group was a kind of antibacterial group. The results of our previous study showed that the 3-COOR substituted 1o 5 benzodiazepines had good bacteriostatic activity and broad spectrum. In this paper, we have designed and synthesized a new type of 1 / 5 benzodiazepines substituted by 2 or 3 diesters and 4 long chain ester groups in order to obtain compounds with high bacteriostatic activity. The structure-activity relationship of the above compounds is also studied systematically in this paper. The main contents of this thesis are as follows: (1) Synthesis of 2-substituted aryl-4-ethyl propionate derivatives with long chain ester structure at C-4: ethyl levulinate, p-substituted benzaldehyde, The substituted o-phenylenediamine was synthesized by hydroxyaldehyde-condensation, nucleophilic addition, dehydration and cyclization. The structures of all compounds were characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, IR, mass spectrometry and elemental analysis. Studies on the Synthesis and Antibacterial activity of Diester based 2o 3-Diester -4-alkyl-1-alkyl-5-benzodiazepines: in this paper, o-phenylenediamine or substituted o-phenylenediamine, dicarbonyl ester compounds and ethyl glyoxylate were used as raw materials. In this paper, a series reaction of one pot and two steps was used to synthesize 30 kinds of 1'5 'benzodiazepines containing 2o 3 diester substituents. All the obtained compounds were characterized by NMR, IR, MS and elemental analysis, and the possible reaction mechanism was proposed. In vitro bacteriostatic tests were carried out on 30 kinds of 2h3- diester-4-alkyl-5-benzodiazepines by filter paper method. The results showed that all the compounds had antimicrobial activities and 24 of them had higher bacteriostatic activities. Especially, the diameter of inhibition circle of compound IVu against Cryptococcus neoformans was 29.27mm. The standard Cryptococcus neoformans and Cryptococcus neoformans clinical beads were tested by MIC with the compound IVu and compared with the standard drug fluconazole. It was found that the MIC value of the compound was higher than that of the standard drug fluconazole. The structure-activity relationship between various substituents and bacteriostatic activities of the compounds was analyzed from the relationship between structure and bacteriostatic activity. The density functional theory (DFT) calculation method in Gaussian 03 quantum chemical program package is used. In this paper, the quantitative calculations of some of the diester containing 2o 3 diester 4 alkyl 1 5 benzodiazepines have been carried out at the level of B3LYP/6-31G group. The relationship between theoretical parameters and bacteriostatic activity was analyzed from the quantitative point of view, and the one-variable equation of quantitative structure-activity relationship was established and verified. The structure-activity relationship can provide theoretical basis for prediction and discovery of compounds with higher activity.
【学位授予单位】：河北师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626;TQ460.1
[Abstract]:1 ~ (5)-benzodiazepines are a class of bioactive molecules containing seven-component nitrogen heterocycles, which have unique physiological and pharmacological activities. It has been shown to have anticonvulsant, antidepressant, insomnia, antianxiety, and calming effects. In recent years, it has been reported that 1o-5-benzodiazepines can also inhibit bacteria and fungi. Therefore, the synthesis and antimicrobial activity of 1C-5-benzodiazepines are one of the hotspots in drug synthesis. Our research group has been devoted to the synthesis and antibacterial activity of 1 ~ 5-benzodiazepines. A variety of novel 1 & 5-benzodiazepines were synthesized. It was found that some of the compounds introduced ester groups into seven heterocyclic compounds had good bacteriostatic activity, that is, ester group was a kind of antibacterial group. The results of our previous study showed that the 3-COOR substituted 1o 5 benzodiazepines had good bacteriostatic activity and broad spectrum. In this paper, we have designed and synthesized a new type of 1 / 5 benzodiazepines substituted by 2 or 3 diesters and 4 long chain ester groups in order to obtain compounds with high bacteriostatic activity. The structure-activity relationship of the above compounds is also studied systematically in this paper. The main contents of this thesis are as follows: (1) Synthesis of 2-substituted aryl-4-ethyl propionate derivatives with long chain ester structure at C-4: ethyl levulinate, p-substituted benzaldehyde, The substituted o-phenylenediamine was synthesized by hydroxyaldehyde-condensation, nucleophilic addition, dehydration and cyclization. The structures of all compounds were characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, IR, mass spectrometry and elemental analysis. Studies on the Synthesis and Antibacterial activity of Diester based 2o 3-Diester -4-alkyl-1-alkyl-5-benzodiazepines: in this paper, o-phenylenediamine or substituted o-phenylenediamine, dicarbonyl ester compounds and ethyl glyoxylate were used as raw materials. In this paper, a series reaction of one pot and two steps was used to synthesize 30 kinds of 1'5 'benzodiazepines containing 2o 3 diester substituents. All the obtained compounds were characterized by NMR, IR, MS and elemental analysis, and the possible reaction mechanism was proposed. In vitro bacteriostatic tests were carried out on 30 kinds of 2h3- diester-4-alkyl-5-benzodiazepines by filter paper method. The results showed that all the compounds had antimicrobial activities and 24 of them had higher bacteriostatic activities. Especially, the diameter of inhibition circle of compound IVu against Cryptococcus neoformans was 29.27mm. The standard Cryptococcus neoformans and Cryptococcus neoformans clinical beads were tested by MIC with the compound IVu and compared with the standard drug fluconazole. It was found that the MIC value of the compound was higher than that of the standard drug fluconazole. The structure-activity relationship between various substituents and bacteriostatic activities of the compounds was analyzed from the relationship between structure and bacteriostatic activity. The density functional theory (DFT) calculation method in Gaussian 03 quantum chemical program package is used. In this paper, the quantitative calculations of some of the diester containing 2o 3 diester 4 alkyl 1 5 benzodiazepines have been carried out at the level of B3LYP/6-31G group. The relationship between theoretical parameters and bacteriostatic activity was analyzed from the quantitative point of view, and the one-variable equation of quantitative structure-activity relationship was established and verified. The structure-activity relationship can provide theoretical basis for prediction and discovery of compounds with higher activity.
【学位授予单位】：河北师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626;TQ460.1
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