C-N链为桥基的邻羟基二苯基桥连化合物合成及抑菌活性研究
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摘要
邻羟基二苯醚类化合物具有优异的抗菌性能,近年的生物信息学研究表明,该类化合物是通过模拟细菌ENR酶的自然作用底物使酶失活,从而破坏和终断了正常的脂肪酸生物合成实现杀菌。研究显示,“邻羟基苯基”分子片段,桥基的类型、结构和形成氢键的能力等对“病原酶- NAD+辅酶-杀菌化合物”三元络合物的形成有重要作用。
鉴于此,本课题以“邻羟苯基”、“卤代邻羟苯基”为母核,根据生物活性叠加原理,选取在抗菌、抗病毒、抗结核及抗肿瘤领域里有一定的生物活性及广阔的应用前景的席夫碱键、苄胺键、酰腙键及含有咪唑环的结构作为桥基,设计并合成以C-N链为桥基的邻羟基二苯基桥连化合物,并进行了抑菌活性测试。根据结构的不同,将化合物进行如下分类:
(1)以水杨醛为原料,经过溴代修饰,制得5-溴代及3,5-二溴代水杨醛,与取代芳胺缩合得到N-苯基-邻羟苯基亚胺类化合物。抑菌活性测试表明:3,5-二溴-水杨醛缩席夫碱类化合物对金黄色葡萄球菌、大肠杆菌、白色念珠菌均具有较强的抑菌活性。
(2)以卤代水杨醛为原料,经与取代芳胺缩合、NaBH4还原,得到N-苯基-卤代邻羟苄胺类化合物。还原反应进程快,产物单一,收率高。抑菌活性测试表明:化合物对白色念球菌、大肠杆菌具有良好的抑菌活性;芳环上引入卤原子的化合物抑菌性能有显著提升。
(3)以水杨酸甲酯为原料,经溴化、肼解与取代芳香醛缩合得到芳基取代-5-溴水杨酰腙类化合物。抑菌活性测试表明:化合物对白色念珠菌、枯草芽孢杆菌的抑菌率高达100%,具有强抑菌活性。构效分析表明,化合物的抑菌活性与Ar环及其取代基性质有关,引入呋喃环、Ar环邻、对位引入-OH、-OCH3等供电基容易导致化合物抑菌活性降低,Ar环的间位引入Cl、Br等卤素原子能够提高化合物的抑菌活性。
(4)以水杨醛和乙二胺为起始原料,经缩合、NaBH4还原,进而与芳醛类化合物缩合关环制得N,N′-二(-2-羟苄基)取代咪唑烷衍生物。结果表明,水杨醛与乙二胺的缩合反应,可专一性地生成对称双缩席夫碱化合物;芳醛上的取代基对缩合关环反应有显著影响,邻、对位吸电基可使芳醛的羰基活化,有利于缩合关环反应的进行,邻、对位供电基可使芳醛的羰基钝化,不利于缩合关环反应进行。抑菌活性测试表明,化合物对不同菌株的抑菌活性具有明显的特异性,对白色念珠菌、大肠杆菌的抑菌率高达100%,具有强抑菌性。
本文总结了抑菌活性和化合物结构之间的关系,为进一步设计具有广谱高效的抗菌型化合物奠定了基础。
o-Hydroxy diphenyl ether compouds have a excellent antibacterial activity, In recent years, bioinformatics research show that they sterilized by simulating nature substrate of bacteria ENR enzyme and restrianing enzyme activity, then destroy and break off biosynthesis of fatty acids. Some research in o-Hydroxy diphenyl ether show that the molecule segment o-Hydroxyphenyl,types of bridged groups and ability of hydrogen bonding, which have a important effect on ternary complex compounds of“pathogen enzyme-NAD+ coenzyme-sterilization compound”.
A series of o-Hydroxyphenyl aryl substituted bridged compounds were designed by combining the molecule segment o-Hydroxyphenyl or halogeno-o-Hydroxyphenyl, by select Schiff base bond, benzylamine bond, hydrazone bond and imidazole ring structure as bridged group which have a wide applying prospect in anbacterial, antivirus, antituberculosis and anti-tumor activity field. Compounds were synthesized and tested in antibacterial activities, then classified according to different structure as follow:
(1) The N-substituted phenyl-o-Hydroxyphenyl Schiff bases were synthesiszed by using salicylaldehyde as raw material, through bromination and condensation with aromatic amines. The test of antibacterial activity showed that 3,5-dibromo substituted compounds have better inhibitory ratio on Staphylococcus aureus, Escherichia coli and Monilia albican.
(2) The N-substituted phenyl-halogeno-o-Hydroxybenzylamines were synthesiszed by using salicylaldehyde as raw material, through condensation with aromatic amines and reduction with NaBH4, respectively. The test of antibacterial activity showed that the compouds have a favorable extent antibacterial activities on Escherichia coli and Monilia albican, their antibacterial activities were enhanced by the substituted halogen groups of Ar-ring.
(3) The o-Hydroxyphenyl aryl substituted hydrazones and their 5-bromo substituted derivatives were synthesiszed by using methyl salicylate as raw material, through bromination, hydrazination and condensation reactions, respectively. The test of antibacterial activity showed that they have 100% inhibitory ratio on Monilia albican and Bacillus subtilis. The analysis of structure activity relationship show that antibacterial activities relate to the kind of Ar-ring and its substituent groups. The antibacterial activities were reduced by electron-donating groups, such as o-,p-OH、-OCH3 of Ar-ring, however, they were enhanced by the m-substituted halogen groups of Ar-ring.
(4)The N,N′-bis(-2-hydroxybenzyl) substituted imidazolidine derivatives were synthesized by using salicylaldehyd as raw materials, through condensation with 1,2-Diaminoethane, reduction with NaBH4 and condensation with aromatic aldehydes, respectively. The result shows that the reaction of salicylaldehyde and 1,2-Diaminoethane singled to obtain the symmetric Schiff base, The condensation activity of Aromatic Aldehyde were obviously affected by the kinds of substituents, the closing reaction of ring could be actived by o-,p-substituted electron-withdrawing groups of aromatic aldehyde and compounds of higher yield were be obtained, but o-,p-substitute electron-donating groups have opposite effects. The test of antibacterial activity showed that they have 100% inhibitory ratio on Monilia albican and Escherichia coli.
The relationship between antibacterial activities and compounds structures were summed up, for establishing a base to design novel bactericide in broad-spectrum with highly active.
鉴于此,本课题以“邻羟苯基”、“卤代邻羟苯基”为母核,根据生物活性叠加原理,选取在抗菌、抗病毒、抗结核及抗肿瘤领域里有一定的生物活性及广阔的应用前景的席夫碱键、苄胺键、酰腙键及含有咪唑环的结构作为桥基,设计并合成以C-N链为桥基的邻羟基二苯基桥连化合物,并进行了抑菌活性测试。根据结构的不同,将化合物进行如下分类:
(1)以水杨醛为原料,经过溴代修饰,制得5-溴代及3,5-二溴代水杨醛,与取代芳胺缩合得到N-苯基-邻羟苯基亚胺类化合物。抑菌活性测试表明:3,5-二溴-水杨醛缩席夫碱类化合物对金黄色葡萄球菌、大肠杆菌、白色念珠菌均具有较强的抑菌活性。
(2)以卤代水杨醛为原料,经与取代芳胺缩合、NaBH4还原,得到N-苯基-卤代邻羟苄胺类化合物。还原反应进程快,产物单一,收率高。抑菌活性测试表明:化合物对白色念球菌、大肠杆菌具有良好的抑菌活性;芳环上引入卤原子的化合物抑菌性能有显著提升。
(3)以水杨酸甲酯为原料,经溴化、肼解与取代芳香醛缩合得到芳基取代-5-溴水杨酰腙类化合物。抑菌活性测试表明:化合物对白色念珠菌、枯草芽孢杆菌的抑菌率高达100%,具有强抑菌活性。构效分析表明,化合物的抑菌活性与Ar环及其取代基性质有关,引入呋喃环、Ar环邻、对位引入-OH、-OCH3等供电基容易导致化合物抑菌活性降低,Ar环的间位引入Cl、Br等卤素原子能够提高化合物的抑菌活性。
(4)以水杨醛和乙二胺为起始原料,经缩合、NaBH4还原,进而与芳醛类化合物缩合关环制得N,N′-二(-2-羟苄基)取代咪唑烷衍生物。结果表明,水杨醛与乙二胺的缩合反应,可专一性地生成对称双缩席夫碱化合物;芳醛上的取代基对缩合关环反应有显著影响,邻、对位吸电基可使芳醛的羰基活化,有利于缩合关环反应的进行,邻、对位供电基可使芳醛的羰基钝化,不利于缩合关环反应进行。抑菌活性测试表明,化合物对不同菌株的抑菌活性具有明显的特异性,对白色念珠菌、大肠杆菌的抑菌率高达100%,具有强抑菌性。
本文总结了抑菌活性和化合物结构之间的关系,为进一步设计具有广谱高效的抗菌型化合物奠定了基础。
o-Hydroxy diphenyl ether compouds have a excellent antibacterial activity, In recent years, bioinformatics research show that they sterilized by simulating nature substrate of bacteria ENR enzyme and restrianing enzyme activity, then destroy and break off biosynthesis of fatty acids. Some research in o-Hydroxy diphenyl ether show that the molecule segment o-Hydroxyphenyl,types of bridged groups and ability of hydrogen bonding, which have a important effect on ternary complex compounds of“pathogen enzyme-NAD+ coenzyme-sterilization compound”.
A series of o-Hydroxyphenyl aryl substituted bridged compounds were designed by combining the molecule segment o-Hydroxyphenyl or halogeno-o-Hydroxyphenyl, by select Schiff base bond, benzylamine bond, hydrazone bond and imidazole ring structure as bridged group which have a wide applying prospect in anbacterial, antivirus, antituberculosis and anti-tumor activity field. Compounds were synthesized and tested in antibacterial activities, then classified according to different structure as follow:
(1) The N-substituted phenyl-o-Hydroxyphenyl Schiff bases were synthesiszed by using salicylaldehyde as raw material, through bromination and condensation with aromatic amines. The test of antibacterial activity showed that 3,5-dibromo substituted compounds have better inhibitory ratio on Staphylococcus aureus, Escherichia coli and Monilia albican.
(2) The N-substituted phenyl-halogeno-o-Hydroxybenzylamines were synthesiszed by using salicylaldehyde as raw material, through condensation with aromatic amines and reduction with NaBH4, respectively. The test of antibacterial activity showed that the compouds have a favorable extent antibacterial activities on Escherichia coli and Monilia albican, their antibacterial activities were enhanced by the substituted halogen groups of Ar-ring.
(3) The o-Hydroxyphenyl aryl substituted hydrazones and their 5-bromo substituted derivatives were synthesiszed by using methyl salicylate as raw material, through bromination, hydrazination and condensation reactions, respectively. The test of antibacterial activity showed that they have 100% inhibitory ratio on Monilia albican and Bacillus subtilis. The analysis of structure activity relationship show that antibacterial activities relate to the kind of Ar-ring and its substituent groups. The antibacterial activities were reduced by electron-donating groups, such as o-,p-OH、-OCH3 of Ar-ring, however, they were enhanced by the m-substituted halogen groups of Ar-ring.
(4)The N,N′-bis(-2-hydroxybenzyl) substituted imidazolidine derivatives were synthesized by using salicylaldehyd as raw materials, through condensation with 1,2-Diaminoethane, reduction with NaBH4 and condensation with aromatic aldehydes, respectively. The result shows that the reaction of salicylaldehyde and 1,2-Diaminoethane singled to obtain the symmetric Schiff base, The condensation activity of Aromatic Aldehyde were obviously affected by the kinds of substituents, the closing reaction of ring could be actived by o-,p-substituted electron-withdrawing groups of aromatic aldehyde and compounds of higher yield were be obtained, but o-,p-substitute electron-donating groups have opposite effects. The test of antibacterial activity showed that they have 100% inhibitory ratio on Monilia albican and Escherichia coli.
The relationship between antibacterial activities and compounds structures were summed up, for establishing a base to design novel bactericide in broad-spectrum with highly active.
引文
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