邻羟苯基芳基桥连化合物的设计、合成及生物活性研究
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摘要
近年来,由于缺乏安全高效的抗菌、抗病毒剂,使得由病菌引起的各类传染病频发。因此研发新型高效抗菌剂是当今国际面临的急迫课题。
本文基于生物信息学和杀菌机理的最新发现,以具有特异性杀菌作用的三氯生为模板分子,设计合成了一系列邻羟苯基芳基桥连化合物,并进行了表征和抗菌活性研究。
首先,合成出3种氯代-邻羟基二苯醚及其系列中间体,用IR、1HNMR和元素分析表征了结构。得出了氯代苯酚与2,5-二氯硝基苯缩合反应的动力学、氯代苯酚结构与反应活性关系、相转移催化剂影响等规律。研究了取代基、金属离子对邻氨基二苯醚重氮盐转化反应的影响。首次推测了金属离子催化下该类重氮盐分子内关环反应的机理。
其次,设计了氯代-邻羟基二苯醚类产品的制备工艺,系统优化了工艺条件,首次将准分子精馏、络合萃取去除重金属离子、多级萃取等技术组合集成,提出“组合纯化技术”,建立了国内首套邻羟基二苯醚类产品制备平台技术。
其三,合成出4种邻羟苯基苄胺化合物及其系列中间体,用IR、1HNMR表征了结构。研究了卤苄与邻氨基苯甲醚的N-苄基化反应、邻苄胺基苯甲醚的脱甲基化反应,揭示了取代基的给电性、反应介质等对反应活性、条件和产品收率的影响规律。
其四,抑菌试验表明,三氯生对大肠杆菌、金葡球菌、白念珠菌、铜绿假单胞菌均具有强抑菌性,2-苄胺基苯酚、2-(4-氯苄胺基)苯酚对白念珠菌、大肠杆菌、金葡球菌具有强抑菌性,2-(4-羟基苄胺基)苯酚对大肠杆菌、金葡球菌具有强抑菌性。经小鼠、大鼠急性经口毒性试验,小鼠骨髓嗜多染红细胞微核试验,皮肤刺激试验,亚急性毒性试验,表明三氯生低毒、无致微核和刺激作用。
In recent years, various infectious diseases caused by germina broke frequently due to lack of safe and effective microbicides. Therefore, to research new efficient antibacterial agents has become an urgent international issue.
In this paper, triclosan with specific sterilization as template molecule, a series of o-hydroxylphenyl-aryl bridge compounds were designed and synthesized based on bioinformatics and bactericidal mechanism. Furthermore, the characterization and antibacterial activities of the compounds were studied.
Firstly, three compounds of chloro-o-hydroxyl-diphenyl-ether and their intermediates were synthesized. The characterization was confirmed by IR, 1HNMR and element analysis. The reaction kinetics of chloro-phenol with 2,5-dichloro-nitrobenzene, the relation between the structure of chloro-phenol and reaction activity, the rules of phase transfer catalyst effection were obtained. The conversion effection of the substituted groups, metal cations on o-amino-diphenyl ether diazonium salt were studied. The intramolecular cyclization mechanism of this kind diazonium salt under metal cation as catalyst were proposed firstly.
Secondly, the process of preparing chloro-o-hydroxyl-dipheyl ether was designed in this paper. Combination purification technology include excimer rectify, complex extraction, removal of metal cation, muti-step extraction was proposed firstly. As a result, the first technology for preparing o-hydroxyl-dipheyl ether was built in domestic.
Thirdly, the four compounds of o-hydroxylphenyl-benzyl-amine and their intermediates were synthesized, and their character was determined by IR, 1HNMR. The reaction of benzyl halide with o-amino-phenyl-methyl ether to produce N-benzyl compounds, and demethylation of o-benzyl-amino-phenyl-methyl ether were studied. The rules of the effection of nucleophile of substituted groups, the reaction media, conditions on the yields of products were studied also.
Finally, the tests of antibacterial showed that colibacillus, staphylococcus aureus, candida albicans, pseudomonas aeruginosa were restrained by triclosan; candida albicans, colibacillus, staphylococcus aureus were restrained by 2-amino-benzyl- -phenol, 2-(4-chlorobenzylamino)-phenol; colibacillus, staphylococcus aureus were restrained by 2-(4-hydroxyl)benzylamino-phenol also. The oral test of mice and rats, bone marrow in red cell nuclear test of mice, skin irritation test, etc. showed that triclosan is of low poison and no irritation.
本文基于生物信息学和杀菌机理的最新发现,以具有特异性杀菌作用的三氯生为模板分子,设计合成了一系列邻羟苯基芳基桥连化合物,并进行了表征和抗菌活性研究。
首先,合成出3种氯代-邻羟基二苯醚及其系列中间体,用IR、1HNMR和元素分析表征了结构。得出了氯代苯酚与2,5-二氯硝基苯缩合反应的动力学、氯代苯酚结构与反应活性关系、相转移催化剂影响等规律。研究了取代基、金属离子对邻氨基二苯醚重氮盐转化反应的影响。首次推测了金属离子催化下该类重氮盐分子内关环反应的机理。
其次,设计了氯代-邻羟基二苯醚类产品的制备工艺,系统优化了工艺条件,首次将准分子精馏、络合萃取去除重金属离子、多级萃取等技术组合集成,提出“组合纯化技术”,建立了国内首套邻羟基二苯醚类产品制备平台技术。
其三,合成出4种邻羟苯基苄胺化合物及其系列中间体,用IR、1HNMR表征了结构。研究了卤苄与邻氨基苯甲醚的N-苄基化反应、邻苄胺基苯甲醚的脱甲基化反应,揭示了取代基的给电性、反应介质等对反应活性、条件和产品收率的影响规律。
其四,抑菌试验表明,三氯生对大肠杆菌、金葡球菌、白念珠菌、铜绿假单胞菌均具有强抑菌性,2-苄胺基苯酚、2-(4-氯苄胺基)苯酚对白念珠菌、大肠杆菌、金葡球菌具有强抑菌性,2-(4-羟基苄胺基)苯酚对大肠杆菌、金葡球菌具有强抑菌性。经小鼠、大鼠急性经口毒性试验,小鼠骨髓嗜多染红细胞微核试验,皮肤刺激试验,亚急性毒性试验,表明三氯生低毒、无致微核和刺激作用。
In recent years, various infectious diseases caused by germina broke frequently due to lack of safe and effective microbicides. Therefore, to research new efficient antibacterial agents has become an urgent international issue.
In this paper, triclosan with specific sterilization as template molecule, a series of o-hydroxylphenyl-aryl bridge compounds were designed and synthesized based on bioinformatics and bactericidal mechanism. Furthermore, the characterization and antibacterial activities of the compounds were studied.
Firstly, three compounds of chloro-o-hydroxyl-diphenyl-ether and their intermediates were synthesized. The characterization was confirmed by IR, 1HNMR and element analysis. The reaction kinetics of chloro-phenol with 2,5-dichloro-nitrobenzene, the relation between the structure of chloro-phenol and reaction activity, the rules of phase transfer catalyst effection were obtained. The conversion effection of the substituted groups, metal cations on o-amino-diphenyl ether diazonium salt were studied. The intramolecular cyclization mechanism of this kind diazonium salt under metal cation as catalyst were proposed firstly.
Secondly, the process of preparing chloro-o-hydroxyl-dipheyl ether was designed in this paper. Combination purification technology include excimer rectify, complex extraction, removal of metal cation, muti-step extraction was proposed firstly. As a result, the first technology for preparing o-hydroxyl-dipheyl ether was built in domestic.
Thirdly, the four compounds of o-hydroxylphenyl-benzyl-amine and their intermediates were synthesized, and their character was determined by IR, 1HNMR. The reaction of benzyl halide with o-amino-phenyl-methyl ether to produce N-benzyl compounds, and demethylation of o-benzyl-amino-phenyl-methyl ether were studied. The rules of the effection of nucleophile of substituted groups, the reaction media, conditions on the yields of products were studied also.
Finally, the tests of antibacterial showed that colibacillus, staphylococcus aureus, candida albicans, pseudomonas aeruginosa were restrained by triclosan; candida albicans, colibacillus, staphylococcus aureus were restrained by 2-amino-benzyl- -phenol, 2-(4-chlorobenzylamino)-phenol; colibacillus, staphylococcus aureus were restrained by 2-(4-hydroxyl)benzylamino-phenol also. The oral test of mice and rats, bone marrow in red cell nuclear test of mice, skin irritation test, etc. showed that triclosan is of low poison and no irritation.
引文
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