本文選題：十六元大環(huán)內(nèi)酯 + 側(cè)鏈��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年博士論文

【摘要】：十六元大環(huán)內(nèi)酯類抗生素是大環(huán)內(nèi)酯類抗生素家族的重要組成部分,主要代表物為交沙霉素和泰樂霉素。十六元大環(huán)內(nèi)酯的研究進(jìn)展相對于十四元大環(huán)內(nèi)酯落后了很多,但是因其結(jié)構(gòu)差異,相對于十四元大環(huán)內(nèi)酯有很多特點(diǎn)：胃腸刺激��；沒有藥物相互作用；無誘導(dǎo)耐藥和泵出耐藥。 為了找到可以找到新的有好的抗菌活性的大環(huán)內(nèi)酯實(shí)體,我們選擇交沙霉素為先導(dǎo)化合物,因?yàn)樗鼪]有泵出耐藥機(jī)制,且成分單一結(jié)構(gòu)明確。交沙霉素在臨床上主要用來醫(yī)治革蘭氏陽性菌和支原體感染,其結(jié)構(gòu)特點(diǎn)為母體是一個含共軛雙鍵的十六元內(nèi)酯環(huán),其5-位連接了一個D-mycaminosyl-L-mycarose結(jié)構(gòu)的二糖。這個二糖結(jié)構(gòu)深入細(xì)菌肽轉(zhuǎn)移酶中心,與23SrRNA中的A2058之間形成氫鍵,從而起到抑菌作用。同時十六元大環(huán)內(nèi)酯6-位還含有一個重要的乙醛基,在十六元大環(huán)內(nèi)酯和靶點(diǎn)結(jié)合過程中,它會和N6的A2103(2062)形成一個共價鍵。 這篇論文的工作意在運(yùn)用以結(jié)構(gòu)修飾為基礎(chǔ)的構(gòu)效關(guān)系研究,力圖找到對敏感菌和耐藥菌都有高活性的十六元大環(huán)內(nèi)酯實(shí)體,并探討其構(gòu)效關(guān)系,為發(fā)現(xiàn)藥物候選物研究提供理論和實(shí)驗(yàn)依據(jù)。 1,一系列新的4'-位羥基修飾的去碳酶糖交沙霉素衍生物的設(shè)計(jì)、合成及抗菌活性研究 通過對去碳酶糖交沙霉素4’-位羥基進(jìn)行結(jié)構(gòu)修飾,合成了14個樣品化合物,并進(jìn)行了體外活性測試�；钚越Y(jié)果表明,β-位單取代的丙酸酯衍生物15和16,對S. aureus (MSSA)和S. epidermidis (MSSE)菌種表現(xiàn)出了最好的抗菌活性。 2,一系列新的含6-位氮雜側(cè)鏈的交沙霉素衍生物的設(shè)計(jì)、合成及抗菌活性研究 通過還原氨化反應(yīng),用含各種芳雜環(huán)的胺和交沙霉素的6-位乙醛基進(jìn)行反應(yīng),得到了15個含氮雜芳雜環(huán)側(cè)鏈的交沙霉素衍生物,并進(jìn)行了體外活性測試�；钚越Y(jié)果表明,所合成樣品都沒有或表現(xiàn)出較弱的抗菌活性,說明這種結(jié)構(gòu)修飾方法對于十六元大環(huán)內(nèi)酯類結(jié)構(gòu)改造是不成功的。 3,一系列新的去碳酶糖交沙霉素α,β-不飽和羧酸衍生物的設(shè)計(jì)、合成及抗菌活性研究 通過Homer-Wadsworth-Emmons反應(yīng),將去碳酶糖交沙霉素的6一位乙醛基轉(zhuǎn)化成α,β-不飽和羧酸衍生物,共得到了11個樣品,并進(jìn)行了體外活性測試�；钚越Y(jié)果表明,α,β-不飽和羧酸芐基酯43b和43e對敏感菌和耐藥菌都表現(xiàn)出了優(yōu)異的抗菌活性。 4,一系列新的交沙霉素α,β-不飽和羰基衍生物的設(shè)計(jì)、合成及抗菌活性研究 在上一步研究的基礎(chǔ)上,通過Homer-Wadsworth-Emmons反應(yīng),將交沙霉素的6-位乙醛基轉(zhuǎn)化成α,β-不飽和羰基衍生物,共得到了14個樣品,其活性正在檢查中。 5,一系列新的去碳酶糖交沙霉素α,β-不飽和羧酸酯4’-位羥基修飾的衍生物的設(shè)計(jì)、合成及抗菌活性研究 綜合前面的工作,將α,β-不飽和羧酸芐基酯43b和43e的4’-位羥基進(jìn)行結(jié)構(gòu)修飾,共得到了11個樣品,其活性正在檢查中。 6,兩個新的氮苷交沙霉素α,β-不飽和羧酸芐基酯的設(shè)計(jì)、合成及抗菌活性研究 為了擴(kuò)大化合物多樣性,選擇用電子等排的氮苷取代原十六元大環(huán)內(nèi)酯的氧苷,合成了兩個新的氮苷交沙霉素α,β-不飽和羧酸芐基酯化合物,其活性正在檢查中。
[Abstract]:The sixteen major macrolide antibiotics are an important part of the family of macrolide antibiotics. The main representative of the macrolide antibiotic family is azosomycin and tylosin. The research progress of sixteen yuan macrolide is far behind the fourteen yuan macrolide, but because of its structural difference, there are a lot of characteristics: Fourteen yuan macrolide: gastrointestinal spines. There was no drug interaction, no induced resistance and drug resistance.
In order to find a new macrolide body with good antibacterial activity, we choose the lead compound with AC, because it does not pump the resistance mechanism, and the composition is unambiguous. The sixteen membered lactone ring of the double bond, its 5- position connected with a two sugar of a D-mycaminosyl-L-mycarose structure. This two sugar structure goes deep into the center of the bacterial peptide transferase and forms a hydrogen bond with the A2058 in 23SrRNA. Meanwhile, the 6- bit of sixteen yuan macrolide also contains an important acetaldehyde group, at sixteen yuan macrolide and In the process of target binding, it will form a covalent bond with N6's A2103 (2062).
The purpose of this paper is to study the structure effect relationship based on structural modification, trying to find sixteen macrolide entity with high activity to both sensitive and resistant bacteria, and to explore its structure-activity relationship, which provides theoretical and experimental basis for the discovery of drug candidates.
1, a series of new 4'- hydroxyl modified decarbonylated carbohydrate derivatives, their design, synthesis and antibacterial activity.
14 sample compounds were synthesized by modifying the 4 '- hydroxyl group of carboxorxormixin, and the activity test was carried out in vitro. The activity results showed that the beta - substituted propionate derivatives were 15 and 16, and showed the best antibacterial activity to S. aureus (MSSA) and S. epidermidis (MSSE) strains.
2, design, synthesis and antibacterial activity of a series of new derivatives of 6- containing heterozygous side chains.
By reacting the ammoniation reaction, 15 aza heterocyclic heterocyclic heterocyclic side chains were obtained by the reaction of amines containing a variety of aromatic heterocyclic amines and the 6- acetaldehyde group of oxarvin. The activity test was carried out in vitro. The results showed that the synthesized samples had no or weaker antibacterial activity, indicating the structural modification method. The structural modification of sixteen macrolides is unsuccessful.
3, the design, synthesis and antibacterial activity of a series of new decarboxylic acid, saccharin, and its derivatives.
A total of 11 samples were obtained by converting 6 one acetaldehyde group of glyoxalin de carbohydrate to alpha, beta unsaturated carboxylic acid derivatives by Homer-Wadsworth-Emmons reaction. The activity test was carried out in vitro. The results showed that alpha, beta unsaturated carboxylic acid benzyl ester 43b and 43E showed excellent antibacterial activity to both sensitive and resistant bacteria.
4, a series of new design, synthesis and antibacterial activity of a novel oxalin a, beta unsaturated carbonyl derivative.
On the basis of the previous study, through the Homer-Wadsworth-Emmons reaction, the 6- bit acetaldehyde group of oxalin was converted into alpha, beta unsaturated carbonyl derivatives, and 14 samples were obtained. The activity is being examined.
5, design, synthesis and antibacterial activity of a series of new derivatives of decarboxylic acid, saccharin, alpha, beta unsaturated carboxylic ester, 4 '- hydroxyl group.
In the previous work, we modified the structure of the 4 '- hydroxyl group of benzyl ester of 43b and 43E, and obtained 11 samples. Their activity is being examined.
Design, synthesis and antibacterial activity of 6, two new nitroside glycosides, benzyl esters of alpha, beta unsaturated carboxylic acid,
In order to expand the compound diversity, two new azoside azithromycin alpha, beta unsaturated carboxylic acid benzyl ester compounds were synthesized by replacing the oxygen glycosides of the original sixteen yuan macrolide with the nitrogen glycosides of the electron, and the activity was being examined.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R914

【參考文獻(xiàn)】

相關(guān)期刊論文 前9條

1 程書權(quán);大環(huán)內(nèi)酯類抗生素的研究與應(yīng)用新探[J];國外醫(yī)藥(抗生素分冊);2002年01期

2 馬培奇;大環(huán)內(nèi)酯類抗生素臨床應(yīng)用進(jìn)展[J];國外醫(yī)藥(抗生素分冊);2002年03期

3 馬恩龍,王澈,王敏偉;大環(huán)內(nèi)酯類抗生素免疫調(diào)節(jié)作用的研究進(jìn)展[J];國外醫(yī)藥(抗生素分冊);2003年01期

4 馬培奇;telithromycin藥學(xué)特性及其臨床地位[J];國外醫(yī)藥(抗生素分冊);2003年01期

5 楊慧,沈敘莊;肺炎鏈球菌對于大環(huán)內(nèi)酯類抗生素的耐藥[J];國外醫(yī)藥(抗生素分冊);2005年02期

6 黎家慶,蘇中杰;紅霉素對消化道動力的影響[J];醫(yī)學(xué)綜述;1999年12期

7 張石革,馬國輝;第2代大環(huán)內(nèi)酯類抗生素的進(jìn)展[J];中國藥業(yè);2003年04期

8 王建強(qiáng);馬淑濤;;16元大環(huán)內(nèi)酯類抗生素的研究進(jìn)展[J];中國藥學(xué)雜志;2006年24期

9 柴棟,王睿,裴斐,陳遷,方翼,劉皈陽;大環(huán)內(nèi)酯類藥物對銅綠假單胞菌生物被膜的影響[J];中華醫(yī)學(xué)雜志;2001年15期

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