【摘要】：1,5-苯并二氮雜卓類化合物是一類含有七元氮雜環(huán)的生物活性分子,具有獨(dú)特的生理活性及藥理活性。研究表明其具有抗驚厥、抗抑郁、治療失眠、抗焦慮、和鎮(zhèn)定等作用。近年來(lái),多有研究報(bào)道1,5-苯并二氮雜卓還具有抑制細(xì)菌與真菌等作用。因此,1,5-苯并二氮雜卓類化合物的合成及抑菌活性的研究是藥物合成研究的熱點(diǎn)之一。本課題組一直致力于1,5-苯并二氮雜卓類化合物的合成及抑菌活性的研究。合成了多種新型1,5-苯并二氮雜卓類化合物,研究發(fā)現(xiàn)部分化合物在七元雜環(huán)上引入酯基具有很好的抑菌活性,即酯基是一種抑菌活性基團(tuán)。本課題組前期研究結(jié)果表明:3-COOR取代的1,5-苯并二氮雜卓具有很好的抑菌活性和生物廣譜性,因此本文設(shè)計(jì)合成了2,3位雙酯基及4位長(zhǎng)鏈酯基取代的新型1,5-苯并二氮雜卓類化合物,以期得到具有較高抑菌活性的化合物。本文還對(duì)上述化合物的構(gòu)效關(guān)系進(jìn)行了較為系統(tǒng)的研究。本論文的主要研究?jī)?nèi)容具體如下:1、C-4位上長(zhǎng)鏈酯基結(jié)構(gòu)的2-取代芳基-4-丙酸乙酯基-1,5-苯并二氮雜卓衍生物的合成:以乙酰丙酸乙酯、對(duì)位取代的苯甲醛、取代的鄰苯二胺為原料,經(jīng)羥醛縮合,親核加成,脫水,環(huán)合等反應(yīng)合成了7種未見(jiàn)文獻(xiàn)報(bào)道的亞胺結(jié)構(gòu)的2-取代芳基-4-丙酸乙酯基-1,5-苯并二氮雜卓衍生物。所有化合物的結(jié)構(gòu)經(jīng)核磁氫譜、碳譜、紅外、質(zhì)譜、元素分析表征,確定該類化合物的結(jié)構(gòu)正確。2、雙酯基結(jié)構(gòu)的2,3-二酯基-4-烷基-1,5-苯并二氮雜卓的合成及抑菌活性研究:本文以鄰苯二胺或取代的鄰苯二胺、二羰基酯化合物、乙醛酸乙酯為原料,通過(guò)一鍋兩步串聯(lián)反應(yīng)合成了30種含有2,3位雙酯基取代的1,5-苯并二氮雜卓類化合物。所有得到的化合物經(jīng)核磁氫譜、核磁碳譜、紅外光譜、質(zhì)譜、元素分析等表征手段確定結(jié)構(gòu)正確,并提出了可能的反應(yīng)機(jī)理。采用濾紙片法將合成的30種2,3-二酯基-4-烷基-1,5-苯并二氮雜卓進(jìn)行了體外抑菌測(cè)試,研究表明所有化合物均具有抑菌活性,其中24種化合物具有較高的抑菌活性,尤其是化合物IVu對(duì)標(biāo)準(zhǔn)新生隱球菌的抑菌圈直徑可達(dá)29.27mm。將化合物IVu對(duì)標(biāo)準(zhǔn)新生隱球菌和新生隱球菌臨床珠進(jìn)行了MIC測(cè)試并與標(biāo)準(zhǔn)藥物氟康唑?qū)Ρ?發(fā)現(xiàn)其MIC值大于標(biāo)準(zhǔn)藥物氟康唑,可作為抑真菌先導(dǎo)化合物,用于藥物開(kāi)發(fā)。3、從結(jié)構(gòu)與抑菌活性關(guān)系分析了化合物的多種取代基團(tuán)與抑菌活性之間的構(gòu)效關(guān)系;采用Gaussian 03量子化學(xué)程序包中密度泛函理論DFT計(jì)算方法,在B3LYP/6-31G基組水平上對(duì)部分所合成的含有雙酯基的2,3-二酯基-4-烷基-1,5-苯并二氮雜卓類化合物進(jìn)行了量化計(jì)算,從定量角度分析了相關(guān)理論參數(shù)與抑菌活性的關(guān)系,建立了定量構(gòu)效關(guān)系一元方程,并對(duì)此進(jìn)行了驗(yàn)證。該構(gòu)效關(guān)系建立可為預(yù)測(cè)、發(fā)現(xiàn)活性更高的化合物提供理論依據(jù)。
[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.
【學(xué)位授予單位】：河北師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：O626;TQ460.1

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