以生物活性为指导的十六元大环内酯交沙霉素结构改造及构效关系研究

发布时间：2018-06-23 23:03

本文选题：十六元大环内酯 + 侧链　；参考：《北京协和医学院》2014年博士论文

【摘要】：十六元大环内酯类抗生素是大环内酯类抗生素家族的重要组成部分,主要代表物为交沙霉素和泰乐霉素。十六元大环内酯的研究进展相对于十四元大环内酯落后了很多,但是因其结构差异,相对于十四元大环内酯有很多特点：胃肠刺激小；没有药物相互作用；无诱导耐药和泵出耐药。为了找到可以找到新的有好的抗菌活性的大环内酯实体,我们选择交沙霉素为先导化合物,因为它没有泵出耐药机制,且成分单一结构明确。交沙霉素在临床上主要用来医治革兰氏阳性菌和支原体感染,其结构特点为母体是一个含共轭双键的十六元内酯环,其5-位连接了一个D-mycaminosyl-L-mycarose结构的二糖。这个二糖结构深入细菌肽转移酶中心,与23SrRNA中的A2058之间形成氢键,从而起到抑菌作用。同时十六元大环内酯6-位还含有一个重要的乙醛基,在十六元大环内酯和靶点结合过程中,它会和N6的A2103(2062)形成一个共价键。这篇论文的工作意在运用以结构修饰为基础的构效关系研究,力图找到对敏感菌和耐药菌都有高活性的十六元大环内酯实体,并探讨其构效关系,为发现药物候选物研究提供理论和实验依据。 1,一系列新的4'-位羟基修饰的去碳酶糖交沙霉素衍生物的设计、合成及抗菌活性研究通过对去碳酶糖交沙霉素4’-位羟基进行结构修饰,合成了14个样品化合物,并进行了体外活性测试。活性结果表明,β-位单取代的丙酸酯衍生物15和16,对S. aureus (MSSA)和S. epidermidis (MSSE)菌种表现出了最好的抗菌活性。 2,一系列新的含6-位氮杂侧链的交沙霉素衍生物的设计、合成及抗菌活性研究通过还原氨化反应,用含各种芳杂环的胺和交沙霉素的6-位乙醛基进行反应,得到了15个含氮杂芳杂环侧链的交沙霉素衍生物,并进行了体外活性测试。活性结果表明,所合成样品都没有或表现出较弱的抗菌活性,说明这种结构修饰方法对于十六元大环内酯类结构改造是不成功的。 3,一系列新的去碳酶糖交沙霉素α,β-不饱和羧酸衍生物的设计、合成及抗菌活性研究通过Homer-Wadsworth-Emmons反应,将去碳酶糖交沙霉素的6一位乙醛基转化成α,β-不饱和羧酸衍生物,共得到了11个样品,并进行了体外活性测试。活性结果表明,α,β-不饱和羧酸苄基酯43b和43e对敏感菌和耐药菌都表现出了优异的抗菌活性。 4,一系列新的交沙霉素α,β-不饱和羰基衍生物的设计、合成及抗菌活性研究在上一步研究的基础上,通过Homer-Wadsworth-Emmons反应,将交沙霉素的6-位乙醛基转化成α,β-不饱和羰基衍生物,共得到了14个样品,其活性正在检查中。 5,一系列新的去碳酶糖交沙霉素α,β-不饱和羧酸酯4’-位羟基修饰的衍生物的设计、合成及抗菌活性研究综合前面的工作,将α,β-不饱和羧酸苄基酯43b和43e的4’-位羟基进行结构修饰,共得到了11个样品,其活性正在检查中。 6,两个新的氮苷交沙霉素α,β-不饱和羧酸苄基酯的设计、合成及抗菌活性研究为了扩大化合物多样性,选择用电子等排的氮苷取代原十六元大环内酯的氧苷,合成了两个新的氮苷交沙霉素α,β-不饱和羧酸苄基酯化合物,其活性正在检查中。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914

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