【摘要】：隨著多重耐藥菌的不斷出現(xiàn),細(xì)菌耐藥性的蔓延已經(jīng)成為危害人類健康的重大問題。絲狀溫度敏感蛋白FtsZ是細(xì)菌分裂過程中最重要的蛋白之一,同時(shí)也是是哺乳動(dòng)物p-微管蛋白結(jié)構(gòu)和功能上的類似物。p-微管蛋白已經(jīng)成功用于抗癌藥物的研發(fā),這表明FtsZ蛋白也很有希望成為抗菌藥物研發(fā)的新靶點(diǎn)。目前為止,人們已經(jīng)發(fā)現(xiàn)了許多通過抑制FtsZ蛋白來影響細(xì)胞分裂的化合物。然而,很少有抑制劑能夠在體內(nèi)表現(xiàn)出優(yōu)良的抗菌活性,也沒有抑制劑進(jìn)入臨床研究。3-MBA的衍生物PC190723是第一個(gè)被報(bào)道的具有優(yōu)良體內(nèi)活性的抑制劑,是FtsZ蛋白抑制劑研究中的熱點(diǎn)。 本論文的研究選取3-MBA作為起點(diǎn),在3-MBA衍生物構(gòu)效關(guān)系的基礎(chǔ)上,以計(jì)算機(jī)輔助藥物設(shè)計(jì)為指導(dǎo),結(jié)合PC190723和金黃色葡萄球菌FtsZ蛋白的共結(jié)晶結(jié)構(gòu),根據(jù)生物電子等排體原理,設(shè)計(jì)并合成了兩類具有新骨架的3-MBA衍生物,主要探索了在3-MBA的4位和5位并入苯環(huán)或雜環(huán)時(shí)對(duì)其抗菌活性和靶向活性的影響。 本論文中系列一的目標(biāo)化合物分別通過Stobbe縮合、環(huán)化反應(yīng)、萘酚的乙�；�、威廉姆斯醚合成等6步反應(yīng)合成得到。系列二的目標(biāo)化合物分別通過酯化反應(yīng)、酚羥基的保護(hù)、成環(huán)反應(yīng)、威廉姆斯醚合成等8步反應(yīng)合成得到。 本論文以苯唑西林鈉、利奈唑胺和環(huán)丙沙星作為陽性對(duì)照藥物,采用96孔板微量稀釋法測(cè)定了3個(gè)關(guān)鍵中間體和17個(gè)具有新骨架的3-MBA衍生物對(duì)于四種革蘭氏陽性菌和兩種革蘭氏陰性菌的抗菌活性,同時(shí)通過形態(tài)學(xué)的分析測(cè)定了目標(biāo)化合物的靶向活性�；钚詼y(cè)定結(jié)果顯示大部分目標(biāo)化合物的抗菌活性相較于3-MBA稍有提高。關(guān)鍵中間體ZE-A對(duì)于六種菌株的抗菌活性和靶向活性比3-MBA提高了4-16倍�；衔顱1對(duì)于枯草桿菌的抗菌活性及靶向活性均提高了32倍�；衔顰13對(duì)大腸桿菌的抗菌活性及靶向活性比關(guān)鍵中間體DHBA均提高了4倍。 綜上所述,本論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。通過研究,我們發(fā)現(xiàn)當(dāng)3-MBA的4位和5位并入苯環(huán)時(shí),化合物可以更好地與FtsZ蛋白PC位點(diǎn)處結(jié)合,這為以3-MBA為起點(diǎn)的FtsZ蛋白抑制劑構(gòu)效關(guān)系研究提供了新的思路,同時(shí)也證明了FtsZ蛋白是一個(gè)非常有希望的抗菌研發(fā)靶點(diǎn),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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

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本文編號(hào)：2433197