作用于FtsZ蛋白PC位点的新型3-MBA衍生物的合成及抗菌活性研究
发布时间：2019-03-02 15:47
【摘要】：随着多重耐药菌的不断出现,细菌耐药性的蔓延已经成为危害人类健康的重大问题。丝状温度敏感蛋白FtsZ是细菌分裂过程中最重要的蛋白之一,同时也是是哺乳动物p-微管蛋白结构和功能上的类似物。p-微管蛋白已经成功用于抗癌药物的研发,这表明FtsZ蛋白也很有希望成为抗菌药物研发的新靶点。目前为止,人们已经发现了许多通过抑制FtsZ蛋白来影响细胞分裂的化合物。然而,很少有抑制剂能够在体内表现出优良的抗菌活性,也没有抑制剂进入临床研究。3-MBA的衍生物PC190723是第一个被报道的具有优良体内活性的抑制剂,是FtsZ蛋白抑制剂研究中的热点。 本论文的研究选取3-MBA作为起点,在3-MBA衍生物构效关系的基础上,以计算机辅助药物设计为指导,结合PC190723和金黄色葡萄球菌FtsZ蛋白的共结晶结构,根据生物电子等排体原理,设计并合成了两类具有新骨架的3-MBA衍生物,主要探索了在3-MBA的4位和5位并入苯环或杂环时对其抗菌活性和靶向活性的影响。 本论文中系列一的目标化合物分别通过Stobbe缩合、环化反应、萘酚的乙酰化、威廉姆斯醚合成等6步反应合成得到。系列二的目标化合物分别通过酯化反应、酚羟基的保护、成环反应、威廉姆斯醚合成等8步反应合成得到。 本论文以苯唑西林钠、利奈唑胺和环丙沙星作为阳性对照药物,采用96孔板微量稀释法测定了3个关键中间体和17个具有新骨架的3-MBA衍生物对于四种革兰氏阳性菌和两种革兰氏阴性菌的抗菌活性,同时通过形态学的分析测定了目标化合物的靶向活性。活性测定结果显示大部分目标化合物的抗菌活性相较于3-MBA稍有提高。关键中间体ZE-A对于六种菌株的抗菌活性和靶向活性比3-MBA提高了4-16倍。化合物B1对于枯草杆菌的抗菌活性及靶向活性均提高了32倍。化合物A13对大肠杆菌的抗菌活性及靶向活性比关键中间体DHBA均提高了4倍。 综上所述,本论文主要探索了具有新骨架的3-MBA衍生物的抗菌活性以及靶向活性。通过研究,我们发现当3-MBA的4位和5位并入苯环时,化合物可以更好地与FtsZ蛋白PC位点处结合,这为以3-MBA为起点的FtsZ蛋白抑制剂构效关系研究提供了新的思路,同时也证明了FtsZ蛋白是一个非常有希望的抗菌研发靶点,具有很好的研究前景。
[Abstract]:With the emergence of multi-drug-resistant bacteria, the spread of bacterial resistance has become a major problem that endangers human health. FtsZ, a filamentous thermosensitive protein, is one of the most important proteins in the process of bacterial division and is also a structural and functional analogue of mammalian ptubulin. P-tubulin has been successfully used in the research and development of anticancer drugs. This suggests that FtsZ protein is also promising as a new target for antibacterial drug development. So far, many compounds have been found to affect cell division by inhibiting the FtsZ protein. However, few inhibitors showed excellent antibacterial activity in vivo, and no inhibitor entered clinical study. PC190723, a derivative of 3-MBA, was the first reported inhibitor with excellent in vivo activity. It is a hot spot in the research of FtsZ protein inhibitors. In this paper, 3-MBA was chosen as the starting point, based on the structure-activity relationship of 3-MBA derivatives and guided by computer-aided drug design, the co-crystalline structure of PC190723 and FtsZ protein of Staphylococcus aureus was combined. Two kinds of 3-MBA derivatives with new framework were designed and synthesized according to the principle of bielectronic isoplanter. The effects of 4 and 5 sites of 3-MBA on their antibacterial activity and targeting activity were investigated when benzene rings or heterocycles were incorporated into benzene rings. The target compounds in this paper were synthesized by Stobbe condensation cyclization acetylation of naphthol and synthesis of Williams ethers respectively. The target compounds were synthesized by esterification, protection of phenolic hydroxyl group, cyclization, Williams ether synthesis and so on. In this study, benzoxicillin sodium, lienazolamine and ciprofloxacin were used as positive control drugs. The antibacterial activities of three key intermediates and 17 3-MBA derivatives with a new skeleton against four gram-positive bacteria and two gram-negative bacteria were determined by 96-well plate microdilution method. At the same time, the targeting activity of the target compounds was determined by morphological analysis. The results of activity assay showed that the antibacterial activity of most of the target compounds was slightly higher than that of 3-MBA. The antibacterial activity and targeting activity of the key intermediate ZE-A against six strains were 16 times higher than that of 3-MBA. The antibacterial activity and targeting activity of compound B1 against Bacillus subtilis increased 32-fold. The antibacterial activity and targeting activity of compound A13 against Escherichia coli were 4 times higher than that of the key intermediate DHBA. In summary, the antibacterial activity and targeting activity of 3-MBA derivatives with new framework were explored in this paper. Through the study, we found that when the 4 and 5 sites of 3-MBA were incorporated into benzene ring, the compounds could better bind to the PC site of FtsZ protein, which provided a new way to study the structure-activity relationship of FtsZ protein inhibitors starting from 3-MBA. At the same time, it is proved that FtsZ protein is a promising target for antibacterial research and development, and it has a good prospect for research.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96
本文编号：2433197
[Abstract]:With the emergence of multi-drug-resistant bacteria, the spread of bacterial resistance has become a major problem that endangers human health. FtsZ, a filamentous thermosensitive protein, is one of the most important proteins in the process of bacterial division and is also a structural and functional analogue of mammalian ptubulin. P-tubulin has been successfully used in the research and development of anticancer drugs. This suggests that FtsZ protein is also promising as a new target for antibacterial drug development. So far, many compounds have been found to affect cell division by inhibiting the FtsZ protein. However, few inhibitors showed excellent antibacterial activity in vivo, and no inhibitor entered clinical study. PC190723, a derivative of 3-MBA, was the first reported inhibitor with excellent in vivo activity. It is a hot spot in the research of FtsZ protein inhibitors. In this paper, 3-MBA was chosen as the starting point, based on the structure-activity relationship of 3-MBA derivatives and guided by computer-aided drug design, the co-crystalline structure of PC190723 and FtsZ protein of Staphylococcus aureus was combined. Two kinds of 3-MBA derivatives with new framework were designed and synthesized according to the principle of bielectronic isoplanter. The effects of 4 and 5 sites of 3-MBA on their antibacterial activity and targeting activity were investigated when benzene rings or heterocycles were incorporated into benzene rings. The target compounds in this paper were synthesized by Stobbe condensation cyclization acetylation of naphthol and synthesis of Williams ethers respectively. The target compounds were synthesized by esterification, protection of phenolic hydroxyl group, cyclization, Williams ether synthesis and so on. In this study, benzoxicillin sodium, lienazolamine and ciprofloxacin were used as positive control drugs. The antibacterial activities of three key intermediates and 17 3-MBA derivatives with a new skeleton against four gram-positive bacteria and two gram-negative bacteria were determined by 96-well plate microdilution method. At the same time, the targeting activity of the target compounds was determined by morphological analysis. The results of activity assay showed that the antibacterial activity of most of the target compounds was slightly higher than that of 3-MBA. The antibacterial activity and targeting activity of the key intermediate ZE-A against six strains were 16 times higher than that of 3-MBA. The antibacterial activity and targeting activity of compound B1 against Bacillus subtilis increased 32-fold. The antibacterial activity and targeting activity of compound A13 against Escherichia coli were 4 times higher than that of the key intermediate DHBA. In summary, the antibacterial activity and targeting activity of 3-MBA derivatives with new framework were explored in this paper. Through the study, we found that when the 4 and 5 sites of 3-MBA were incorporated into benzene ring, the compounds could better bind to the PC site of FtsZ protein, which provided a new way to study the structure-activity relationship of FtsZ protein inhibitors starting from 3-MBA. At the same time, it is proved that FtsZ protein is a promising target for antibacterial research and development, and it has a good prospect for research.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96
【参考文献】
相关期刊论文 前1条
1 李静;抗菌药物的发展及其细菌耐药性[J];实用药物与临床;2005年05期
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