四唑类新型金属β-内酰胺酶抑制剂及含异噁唑环类异羟肟酸的合成和研究
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摘要
本论文包含两部分。第一部分研究了一类含四唑类新型金属β-内酰胺酶抑制剂；第二部分研究了一类新型含异(口恶)唑的异羟肟酸的PDF抑制剂。
自上世纪30年代发现青霉素类抗生素以来，抗生素便成为人类抗病菌感染的主要前线药物。然而，随着抗生素(青霉素类与头孢类)的广泛应用，耐药菌也随之迅速产生并不断蔓延。病菌产生耐药性的途径之一，便是产生用于破坏β-内酰胺类抗生素的β-内酰胺酶，其中含金属离子的β-内酰胺酶就称为金属β-内酰胺酶。金属β-内酰胺酶能够严重破坏β-内酰胺类抗生素，使之失去抗菌活性而大大降低疗效。传统对付β-内酰胺酶的措施有：其一，寻找新的抗生素；其二，探索并用使细菌停止合成β-内酰胺酶的物质；其三，合并使用对β-内酰胺酶敏感和相对稳定的β-内酰胺酶抑制剂；其四，发展特异性的β-内酰胺酶抑制剂。几十年来，人们不断探索新的特异性金属酶抑制剂，取得了一定成果。到目前为止，已有的金属β-内酰胺酶抑制剂有：巯基乙酸衍生物、硫代吡啶二羧酸衍生物、青霉烷砜类等化合物、碳青霉烯类化合物、头孢烯类等。最近有文献报道包含3-n-丁基-1-苯并吡唑-5-羧酸盐联苯四唑或包含3-n-丁基-1-苯并吡唑-5-乙烷基酯联苯四唑对金属β-内酰胺酶具有抑制作用，而且对其生物活性进行了研究。
四氮唑是一个有着广泛用途的官能团。它不仅在医药方面用作亲油性取代基和羧酸替代物；还作为炸药，照相和信息记录系统等，应用非常广泛。本文在文献工作基础上，对以上化合物进行结构改造，将其中一个苯环换成异(口恶)唑环，设计并合成了一系列化合物，并研究了其生物活性和对金属β-内酰胺酶的抑制作用。
本文以对甲基苯甲醛为起始原料，通过包括锌盐催化的取代腈与叠氮环合反应合成四氮唑，以改进的偶极环加成反应合成了芳香环取代的异(口恶)唑，以及氧化、酯化、羟胺化等10-12步反应，合成了包含四氮唑与芳香环取代的异(口恶)唑的异羟肟酸衍生物。
PDF抑制剂类抗生素是20世纪90年代末在国外新兴起的一个研究热点，因为PDF作为抑菌靶点的生化过程很明确，其晶体结构和活性部位也已经比较清楚，所以PDF抑制剂的研究具有较好的前景。我们选取PDF抑制剂作为研究课题，设计并合成新的化合物，希望能够发现新型结构的先导化合物。
本文以含有苯并噻唑和吲哚的异羟肟酸类化合物为先导化合物，根据它们的构效关系和与PDF受体结合的原理，设计并合成了一类新型的含有异(口恶)唑类异羟肟酸衍生物。
以取代的苯甲醛为起始原料，以改进的偶极环加成反应合成了芳香环取代的异(口恶)唑类中间体化合物，进而通过氧化、酯化、羟胺化等数个步骤得到最终目标产物。通过5步的反应，共合成含异(口恶)唑环异羟肟酸化合物15个，全部为新化合物。用~1HNMR、ESI-MS、IR和元素分析对这些化合物进行了分析，确定了这些化合物的结构。对其进行体外抑菌实验显示多数化合物有一定的抑菌作用。意外地发现这类化合物有很好的降糖效果。
This thesis consists of two parts. PartⅠ: Study on the synthesis of novel metallo-β-lactamase inhibitors in which tetrazole was contained; PartⅡ: Study on the synthesis of a novel class of isoxazole-based hydroxamate as PDF inhibitors.
Withβ-lactam antibiotics by the wider use of the rapid spread of drug resistant. Metallo-β-lactamase type and number has been increasing serious impact on the merit of this kind of antibiotics. Traditional againstβ- lactamases measures are as follows: First, the search for new antibiotics and the other, and explore and make use of bacterialβstop - lactamase substances; Third, the combined use ofβ-lactamase sensitive and relatively stableβ-lactamase inhibitor; Fourth, the development of specificβ-lactamase inhibitors. For decades many experiments show that the development of specific inhibitors of metal has become a top priority. At present, with the characteristics of metallo-β- lactamase inhibitors are thioglycolic acid derivatives, thiosulfate pyridine carboxylic acid derivatives, such as Penicillium n-type oxide compounds, carbapenem compounds, cephalosporins ene and so on. Recently reported in the literature contains 3-n-butyl- 1-benzopyrazole-5-carboxylate diphenyl tetrazolium or contains 3-n-butyl-1-benzo pyrazole -5- ethane-ester diphenyl tetrazolium of metallo-β- lactamase inhibited, and its biological activity was studied, the findings showed that compounds containing tetrazole of metallo-β- lactamases have a certain effect.
Tetrazole is a country with a wider use of functional groups. It is not only in Chinese medicine for lipophilic and carboxylic substituent substitute, but also as explosives, photographs and records information system, is widely used. In this paper, based on their improvement, where a benzene ring was replaced by an isoxazole ring, we synthesized a series of compounds to study their biological activity and the metallo-β- lactamase inhibitor.
P-methylbenzaldehyde was used as the starting material, through 10-12 steps, including zinc catalytic 3+2 reaction of cyanobenzene and azide to form tetrazole, [3+2] cycloaddition of the aromatic cyano-oxide with alkyne to afford isoxazole, and followed by oxidation, esterification,hydroxylamination and finally got our target compounds..
We also took benzothiazole hydroxamic acids as lead compounds, according to their structure-activity relationship as the PDF inhibitors, designed and synthesized a new type of hydroxamic acids in which isoxazole is contained.
Benzaldehyde was used as the starting material, [3+2] cycloaddition was performed to afford isoxazole category,oxidation,esterification and hydroxyl amination were used to get final compounds. 15 new compounds were synthesized and their structures were conformed by NMR, ESI-MS, IR and elemental analysis. Vitro experiments showed that some of the compounds have antibiotic activity. And as a by-gaining, we find that these compound have good activity on hyperglycemic disease.
自上世纪30年代发现青霉素类抗生素以来，抗生素便成为人类抗病菌感染的主要前线药物。然而，随着抗生素(青霉素类与头孢类)的广泛应用，耐药菌也随之迅速产生并不断蔓延。病菌产生耐药性的途径之一，便是产生用于破坏β-内酰胺类抗生素的β-内酰胺酶，其中含金属离子的β-内酰胺酶就称为金属β-内酰胺酶。金属β-内酰胺酶能够严重破坏β-内酰胺类抗生素，使之失去抗菌活性而大大降低疗效。传统对付β-内酰胺酶的措施有：其一，寻找新的抗生素；其二，探索并用使细菌停止合成β-内酰胺酶的物质；其三，合并使用对β-内酰胺酶敏感和相对稳定的β-内酰胺酶抑制剂；其四，发展特异性的β-内酰胺酶抑制剂。几十年来，人们不断探索新的特异性金属酶抑制剂，取得了一定成果。到目前为止，已有的金属β-内酰胺酶抑制剂有：巯基乙酸衍生物、硫代吡啶二羧酸衍生物、青霉烷砜类等化合物、碳青霉烯类化合物、头孢烯类等。最近有文献报道包含3-n-丁基-1-苯并吡唑-5-羧酸盐联苯四唑或包含3-n-丁基-1-苯并吡唑-5-乙烷基酯联苯四唑对金属β-内酰胺酶具有抑制作用，而且对其生物活性进行了研究。
四氮唑是一个有着广泛用途的官能团。它不仅在医药方面用作亲油性取代基和羧酸替代物；还作为炸药，照相和信息记录系统等，应用非常广泛。本文在文献工作基础上，对以上化合物进行结构改造，将其中一个苯环换成异(口恶)唑环，设计并合成了一系列化合物，并研究了其生物活性和对金属β-内酰胺酶的抑制作用。
本文以对甲基苯甲醛为起始原料，通过包括锌盐催化的取代腈与叠氮环合反应合成四氮唑，以改进的偶极环加成反应合成了芳香环取代的异(口恶)唑，以及氧化、酯化、羟胺化等10-12步反应，合成了包含四氮唑与芳香环取代的异(口恶)唑的异羟肟酸衍生物。
PDF抑制剂类抗生素是20世纪90年代末在国外新兴起的一个研究热点，因为PDF作为抑菌靶点的生化过程很明确，其晶体结构和活性部位也已经比较清楚，所以PDF抑制剂的研究具有较好的前景。我们选取PDF抑制剂作为研究课题，设计并合成新的化合物，希望能够发现新型结构的先导化合物。
本文以含有苯并噻唑和吲哚的异羟肟酸类化合物为先导化合物，根据它们的构效关系和与PDF受体结合的原理，设计并合成了一类新型的含有异(口恶)唑类异羟肟酸衍生物。
以取代的苯甲醛为起始原料，以改进的偶极环加成反应合成了芳香环取代的异(口恶)唑类中间体化合物，进而通过氧化、酯化、羟胺化等数个步骤得到最终目标产物。通过5步的反应，共合成含异(口恶)唑环异羟肟酸化合物15个，全部为新化合物。用~1HNMR、ESI-MS、IR和元素分析对这些化合物进行了分析，确定了这些化合物的结构。对其进行体外抑菌实验显示多数化合物有一定的抑菌作用。意外地发现这类化合物有很好的降糖效果。
This thesis consists of two parts. PartⅠ: Study on the synthesis of novel metallo-β-lactamase inhibitors in which tetrazole was contained; PartⅡ: Study on the synthesis of a novel class of isoxazole-based hydroxamate as PDF inhibitors.
Withβ-lactam antibiotics by the wider use of the rapid spread of drug resistant. Metallo-β-lactamase type and number has been increasing serious impact on the merit of this kind of antibiotics. Traditional againstβ- lactamases measures are as follows: First, the search for new antibiotics and the other, and explore and make use of bacterialβstop - lactamase substances; Third, the combined use ofβ-lactamase sensitive and relatively stableβ-lactamase inhibitor; Fourth, the development of specificβ-lactamase inhibitors. For decades many experiments show that the development of specific inhibitors of metal has become a top priority. At present, with the characteristics of metallo-β- lactamase inhibitors are thioglycolic acid derivatives, thiosulfate pyridine carboxylic acid derivatives, such as Penicillium n-type oxide compounds, carbapenem compounds, cephalosporins ene and so on. Recently reported in the literature contains 3-n-butyl- 1-benzopyrazole-5-carboxylate diphenyl tetrazolium or contains 3-n-butyl-1-benzo pyrazole -5- ethane-ester diphenyl tetrazolium of metallo-β- lactamase inhibited, and its biological activity was studied, the findings showed that compounds containing tetrazole of metallo-β- lactamases have a certain effect.
Tetrazole is a country with a wider use of functional groups. It is not only in Chinese medicine for lipophilic and carboxylic substituent substitute, but also as explosives, photographs and records information system, is widely used. In this paper, based on their improvement, where a benzene ring was replaced by an isoxazole ring, we synthesized a series of compounds to study their biological activity and the metallo-β- lactamase inhibitor.
P-methylbenzaldehyde was used as the starting material, through 10-12 steps, including zinc catalytic 3+2 reaction of cyanobenzene and azide to form tetrazole, [3+2] cycloaddition of the aromatic cyano-oxide with alkyne to afford isoxazole, and followed by oxidation, esterification,hydroxylamination and finally got our target compounds..
We also took benzothiazole hydroxamic acids as lead compounds, according to their structure-activity relationship as the PDF inhibitors, designed and synthesized a new type of hydroxamic acids in which isoxazole is contained.
Benzaldehyde was used as the starting material, [3+2] cycloaddition was performed to afford isoxazole category,oxidation,esterification and hydroxyl amination were used to get final compounds. 15 new compounds were synthesized and their structures were conformed by NMR, ESI-MS, IR and elemental analysis. Vitro experiments showed that some of the compounds have antibiotic activity. And as a by-gaining, we find that these compound have good activity on hyperglycemic disease.
引文
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[20]Clements, J. M.; Beckett, R. P.; Brown, A., et al. Antibiotic activity and characterization of BB3497-a novel peptide deformylase inhibitor. Antimicrob Agents Chemother., 2001,45 (2), 563-570.
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[22] Apfel, C; Banner, D.; Bur, D. et al. 2-(2-oxo-l,4-dihydro-2H-quinazolin-3-yl)-and 2-(2,2-dioxo-1, 4-dihydro-2H-2γ-benzo [1,2,6]thiadiazin-3-yl)-N-hydroxy-??acetamides as potent and selective peptide deformylase inhibitors. J. Med. Chem., 2001,44,1847-1852.
[23]Chu, M.; Mierzwa, R.; He, L. et al. Isolation and structure elucidation of two novel defonnylase inhibitors produced by strep tomycesp. Tetrahedron Lett, 2001,42 (21), 3549-3551.
[24]Ayasekera, M.; Kendall, A.; Shammas, R. et al. Novel nonpeptidic inhibitors ofpeptide deformylase. Arch. Biochem. Biophys., 2000, 381 (2), 313-316.
[25]British, B.; Gene, S. Announce the start of human trials for the first-in-classantibiotic BB-83698 [N]. British Biotech News Release, 2002-10-1.
[26] Vicuron Receives Milestone Payment for Novel Peptide Deformylase InhibitorDrug Candidate [N] .Vicuron Company News, 2003-12-4.
[27]Jones, R. N.; Rhomberg, P. R. Comparative spectrum and activity of NVP -PDF386 (VRC4887), a new peptide deformylase inhibitor. J. Antimicrobial Chemother, 2002, 51 (1), 157-161.
[28]Roblin, P. M.; Hammerschlag, M. R. In vitro activity of a new antibiotic NVP-PDF386 (VRC4887) against chlamydia pneumoniae. Antimicrob agents chemother, 2003,47 (4), 1447-1448.
[29]Vicuron Updates on Novartis Peptide Deformylase Inhibitor Program [N].Vicuron Company News, 2005-4-3.
[30] David, O. W. Studies Concerning the Amtibiotic Actinonin Part V. Synthesis of Structural Analogues of Actinonin by the Anhydride-Ester Method. Chem. Sci. Perkin Trans. 1,1975, 846-848.
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[32]王喜梅，施开良。丙二酰二异羟肟酸稀土配合物的结构与性质。中山大学学 报(自然科学版)，2000，39(2)，51-55．
[33]梁兴龙，曾伟，李鸿波等。烷基醚桥连的二异羟肟酸核钴(Ⅱ)配合物的合成 及其氧加合性能研究。四川大学学报(自然科学版)，2001，38(2)，290-294．
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[35]钟琳，周先礼，李建章等。异羟肟酸钻(Ⅱ)配合物的合成及表征。四川大 学学报(自然科学版)，2002，39(1)，92-95．
[36]钟祥，梁娟秋，喻庆华。苯异羟肟酸衍生物抑制胃癌细胞活力的体外实验。 金属学报，1982，18，221-227．
[37]崔美芳，顾翼东，黄永明等。几种异羟肟酸的酸解离常数的测定和W(Ⅳ)- 异羟肟酸配合物的合成及表征。无机化学学报，1991，7，394-396．
[38]杨颍，李青山。芳香异羟肟酸二烃基锡配合物的合成、结构及其抗癌活性 的研究。结构化学，1996，15，163-169．
[39]张为革，刘百里。β-芳胺酮类化合物的设计、合成及抗炎活性研究。沈阳 药科大学学报，2000，17，70-74．
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[43] Mukaiyama, T.; Hoshino, T. The reaction of primary nitroparaffins with isocyanates. J. Am. Chem. Soc, 1960, 82,5339-5342.
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