以FtsZ为靶点的5-甲基菲啶类衍生物的设计、合成和抗菌活性研究

发布时间：2018-07-25 10:32

【摘要】：细菌感染严重威胁着人类健康,随着世界范围内细菌耐药性的出现和蔓延,这种威胁越发严重。因此,具有新颖作用机制及作用靶点的抗菌药物应加快开发,从而有效地控制多药耐药菌的产生和传播。FtsZ是一类高度保守的参与细菌细胞分裂的关键蛋白,已作为新型抗菌靶点受到广泛关注。苯菲啶是血根碱和白屈菜赤碱结构的一个截断形式,许多苯菲啶衍生物被合成。这些被合成的苯菲啶衍生物发挥了较好的抗菌活性,是FtsZ抑制剂。因此,对苯菲啶结构进一步简化和优化,则有可能开发出更为有效的FtsZ抑制剂。通过计算机辅助药物设计软件(symbol 2.0)对苯菲啶结构进行简化和对接研究,发现5-甲基菲啶结构中的季铵盐结构可以结合到FtsZ的GTP结合口袋的尾部,而芳环结构则与Gly46、Gly47和Ala48等氨基酸残基通过疏水作用相结合,从而发挥抑制FtsZ的作用。因此,5-甲基菲啶被选定为先导结构用于结构修饰,合成了 3个系列共22个5-甲基菲啶衍生物,并以血根碱、姜黄素、环丙沙星和苯唑西林钠为阳性对照药,测定了所有合成化合物的抗菌活性和靶向活性,总结如下:(1)5-甲基菲啶类衍生物对枯草芽孢杆菌、耐青霉素金黄色葡萄球菌、敏感化脓性链球菌、耐药化脓性链球菌均表现出了较好的活性,有些甚至比先导化合物血根碱活性要高。对敏感性金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌和表皮葡萄球菌抗菌活性均较差。对大肠杆菌和铜绿假单胞菌基本不显示出抗菌活性。此外,化合物的抗菌活性与靶向活性基本一致。(2)化合物 5A5、5A6、5A8、5B1、5B3、5B6、5C1 和 5C2 对枯草芽孢杆菌的活性最强(MIC = 4 μg/mL),是血根碱、环丙沙星和苯唑西林钠的2倍;5A4、5A7、5A11、5B2、5B4、5B7、5C3和5C4对枯草芽孢杆菌的活性较强(MIC =8μg/mL),与血根碱、环丙沙星和苯唑西林钠相同。(3)化合物5A5、5A6、5B1、5B6、5C1和5C2对耐青霉素金黄色葡萄球菌的活性与先导化合物血根碱相同(MIC = 4μg/mL);化合物5B3对敏感性金黄色葡萄球菌有较好的抗菌活性(MIC = 8 μg/mL)与血根碱和苯唑西林钠相同,化合物5B7对耐甲氧西林金黄色葡萄球菌也显示出一定的抗菌活性(MIC = 16μg/mL);5C1和5C2对耐甲氧西林金黄色葡萄球菌显示出抗菌活性(MIC = 32μg/mL)。(4)大部分目标化合物对于敏感化脓性链球菌和耐药化脓性链球菌的活性相差不多,与先导化合物血根碱相同或有小幅提高。基于上述研究结果,5-甲基菲啶类衍生物的初步构效关系归纳如下:(1)在5-甲基菲啶的2位引入烷基,抗菌活性和靶向活性普遍增强,并且直链烷基的活性好于支链烷基;引入甲氧基和甲硫基保留抗菌活性和靶向活性;引入含卤素基团则降低抗菌活性和靶向活性均下降。(2)在在5-甲基菲啶的4位引入烷基、三氟甲氧基、甲氧基和甲硫基保留或略微增强抗菌活性和靶向活性;引入三氟甲基则活性下降。(3)2位、4位联合修饰的化合物,抗菌活性并没有进一步增强,但是靶向活性略有增强。本论文以FtsZ为靶点,对血根碱和白屈菜赤碱等天然FtsZ抑制剂的结构进行简化和优化,选定5-甲基菲啶作为先导结构进行修饰,设计、合成了 3个系列的5-甲基菲啶衍生物,测定了它们对9种细菌的抗菌活性及靶向活性,对其构效关系进行了初步分析,认为5-甲基菲啶衍生物可作为先导化合物进一步优化,以便发现新型FtsZ抑制剂。因此,本论文的研究结果为新型FtsZ抑制剂的设计、合成提供了新思路和新方法。
[Abstract]:Bacterial infection is a serious threat to human health. With the emergence and spread of bacterial resistance in the world, the threat is more serious. Therefore, antimicrobial agents with novel mechanisms and targets should be developed quickly to effectively control the production and transmission of multidrug resistant bacteria, which are highly conservatively involved in bacterial cells. The key protein of the Division has been widely concerned as a new type of antibacterial target. Phenanthridine is a truncated form of the structure of root alkali and corioferine, and many phenanthridine derivatives have been synthesized. These synthesized phenanthridine derivatives play a good antibacterial activity and are FtsZ suppressant. Therefore, the structure of phenanthridine is further simplified and superior. It is possible to develop a more effective FtsZ inhibitor. The structure of phenanthridine is simplified and butted through computer aided drug design software (symbol 2). It is found that the quaternary ammonium salt structure in the 5- methyl phenanthridine structure can be combined with the tail of the GTP binding pocket of FtsZ, while the aromatic ring structure is with the amino acids such as Gly46, Gly47 and Ala48. The residues are combined by hydrophobicity to inhibit FtsZ. Therefore, 5- methyl phenanthridine is selected as a pilot structure for structural modification, and 3 series of 22 5- methyl phenanthridine derivatives are synthesized, and the antibacterial activities of all synthetic compounds are determined with schien base, curcumin, ciprofloxacin and zoxicillin sodium as the positive control drugs. The properties and target activity were summarized as follows: (1) 5- methyl phenanthridine derivatives showed good activity to Bacillus subtilis, penicillin resistant Staphylococcus aureus, sensitive pyogenic Streptococcus, and drug-resistant Streptococcus pyogenes, some even higher than that of pilot compounds. The antibacterial activity of Staphylococcus aureus and Staphylococcus epidermidis was poor. The antibacterial activity of Escherichia coli and Pseudomonas aeruginosa showed no antibacterial activity. In addition, the antibacterial activity of the compound was basically consistent with the target activity. (2) compound 5A5,5A6,5A8,5B1,5B3,5B6,5C1 and 5C2 had the strongest activity to Bacillus subtilis (MIC = 4 g/mL), which was blood. 2 times the root base, ciprofloxacin and zoxicillin sodium, 5A4,5A7,5A11,5B2,5B4,5B7,5C3 and 5C4 were more active (MIC =8 g/mL) to Bacillus subtilis (MIC =8 mu), which were the same as that of root alkali, ciprofloxacin and oxacillin sodium. (3) the activity of compound 5A5,5A6,5B1,5B6,5C1 and 5C2 to penicillin resistant Staphylococcus aureus was the same as that of the pilot compound (MIC). = 4 mu g/mL); compound 5B3 has better antibacterial activity against Staphylococcus aureus (MIC = 8 g/mL), which is the same as that of root alkali and oxacillin sodium. Compound 5B7 also shows a certain antibacterial activity against methicillin resistant Staphylococcus aureus (MIC = 16 mu g/mL); 5C1 and 5C2 show antibacterial activity against methicillin resistant Staphylococcus aureus. Activity (MIC = 32 mu g/mL). (4) most of the target compounds have little difference between the activity of Streptococcus pyogenes and drug resistant Streptococcus, and the same or small increase with the pilot compound. Based on the results, the preliminary structure-activity relationship of the 5- methyl phenanthridine derivatives is summarized as follows: (1) the introduction of the 2 bits of 5- methylphenanthrene. Alkyl, antibacterial activity and target activity are generally enhanced, and the activity of the alkyl alkyl is better than the chain alkyl; the antibacterial activity and the targeting activity are retained by the introduction of methoxy and methionyl groups, and the introduction of halogen groups reduces the antibacterial activity and the target activity. (2) the introduction of alkyl, three fluoromethoxy, methoxy and methyl sulphur in the 4 position of 5- methyl phenanthrene. The base retained or slightly enhanced the antibacterial activity and the targeting activity; the activity of the introduction of three fluoromethyl decreased. (3) 2, 4 co modified compounds, the antibacterial activity was not further enhanced, but the target activity was slightly enhanced. In this paper, the structure of natural FtsZ inhibitors, such as root alkali and coriobine, was simplified and optimized by FtsZ. 5- methyl phenanthridine was selected as the precursor structure to modify, design and synthesize 3 series of 5- methyl phenanthridine derivatives. The antibacterial activity and target activity of them to 9 bacteria were measured. The structure effect relationship was preliminarily analyzed. It was considered that 5- methyl phenanthridine derivative could be further optimized as a pilot compound to discover new FtsZ inhibition. Therefore, the research results in this paper provide new ideas and new methods for the design and synthesis of new FtsZ inhibitors.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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