邻羟苯基修饰的吡唑类衍生物及其中间体的合成及抑菌活性
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摘要
依据生物活性叠加原理,以邻羟苯基、吡唑、腙(NH-N=)基团为分子核心进行合理组合,设计并合成了N-[(1-芳基-3-苯基-吡唑-4-基)次甲基]-2-羟基苯甲酰肼(I系列)、2-取代苯腙基-3-(2-羟基苯甲酰腙基)-丁酸乙酯(II系列)及1-(2-羟基苯甲酰基)-3-甲基-4-取代苯腙基-吡唑啉酮(III系列)三类、共18种化合物,其中12种化合物未见报道,18种化合物的生物活性均未见报道,18种化合物的结构均经IR、~1HNMR、元素分析等证实。
以芳胺为原料,经重氮化、还原、与苯乙酮缩合、Vilsmeier-Haack反应,制得1-芳基-3-苯基-4-甲酰基吡唑,再与水杨酰肼反应制得N-[(1-芳基-3-苯基-吡唑-4-基)次甲基]-2-羟基苯甲酰肼(I4a-I4f),对制备中间体1-芳基-3-苯基-4-甲酰基吡唑(I3a-I3f)的反应机理进行验证和推理,揭示了闭环反应与1位芳环上取代基电子效应之间的关系规律。
以芳胺为原料,经重氮化、与乙酰乙酸乙酯反应,再与水杨酰肼缩合,制得2-取代苯腙基-3-(2-羟基苯甲酰腙基)-丁酸乙酯(II3a-II3f),经分子内闭环制得1-(2-羟基苯甲酰基)-3-甲基-4-取代苯腙基-吡唑啉酮化合物(III4a-III4f),探讨了制备目标化合物的反应机理,研究表明,介质的酸碱性对II3a-II3f、III4a-III4f的制备有显著影响,酸性介质中,反应难以停留在3a~3f阶段,而是快速闭环生成化合物III4a-III4f,要制备高收率的席夫碱II3a-II3f,反应介质需要控制在中性或弱碱性,制备化合物III4a-III4f最好控制在酸性介质中。
测试表明:质量浓度为0.01%时,N-[(1-芳基-3-苯基-吡唑-4-基)次甲基]-2-羟基苯甲酰肼系列化合物、1-(2-羟基苯甲酰基)-3-甲基-4-取代苯腙基-吡唑啉酮系列化合物对大肠杆菌、白色念珠菌的抑菌率均接近或高达100%,有极强的抑菌活性,对金黄色葡萄球菌的抑菌率均达70%以上,有一定的抑菌活性;2-取代苯腙基-3-(2-羟基苯甲酰腙基)-丁酸乙酯(II3b、II3c)对大肠杆菌的抑菌率高达100%,有极强的抑菌活性,对白色念珠菌、金黄色葡萄球菌的抑菌率均达70%以上,有一定的抑菌活性。
构效关系表明:三类化合物的抑菌活性均与芳环上的取代基性质有关,苯环中引入-OCH_3、-NO_2、-CH_3、导致化合物抑菌活性降低,且引入-OCH_3、-CH_3、的化合物较-NO_2的抑菌活性更低;苯环中引入Cl、Br等卤素原子,可显著提高化合物的抑菌活性,且对位引入卤原子的化合物均较间位的抑菌活性更佳。此外,关环前后II3a-II3f、III4a-III4f的抑菌活性有显著变化,与关环前系列化合物II3a~II3f相比,形成吡唑啉酮环后的化合物III4a-III4f的抑菌活性普遍显著提高。
Eighteen compounds were designed and synthesized by combining o-hydroxyl pheny、pyrazole and phenylhydrazone group, according to the superposition principle of biological activities. Twelve compounds and antibacterial-activity of eighteen compounds have not been reported so far. The structures of all compounds were confirmed by 1H NMR、IR and elemental analysis.
Substituted aniline was diazotized and subsequently reduced to give substituted phenylhydrazine, acetophenone arylhydrazone were obtained by the condensation of acetophenone with substituted phenylhydrazine, reacted with N,N-dimethylformamide、phosphorus oxychloride, l-aryl-3-phenyl-4-formylpyrazoles were obtained. Then reacted with salicylic hydrazide to obtain N-[(1-aryl-3-phenyl-pyrazol-4-yl)methylene]-2-hydroxybenzohydrazide (I4a-I4f), verified and deduced the reaction mechanism of acquiring the1-aryl-3-phenyl-4-formyl-pyrazoles(I3a-I3f), revealed the realationships between cyclization reaction activities and electronic effect of the 1- phenyl ring substituent.
Substituted aniline was diazotized and subsequently reacted with ethylacetoacetate, then condensed with salicylic hydrazide to obtain 3-(2-hydroxybenzoylhydrazono)-2-(2-phenylhydrazono)-ethyl butanoates(II3a-II3f). 1-(2-Hydroxybenzoyl)-3-methyl-4-substitued phenylhydrazono-pyrazolones(III4a-III4f) were acquired by intramolecular cyclization reaction of compounds II3a-II3f. The reaction mechanism of acquireing target compounds showed compounds II3a-II3f were difficult to maintain in acidic medium, but generated compounds III4a-III4f with rapid cyclization. So, preparation of compounds II3a-II3f should be in neutral or weak alkaline solution, but preparation of compounds II3a-II3f had better be in the acdic medium.
The result of preliminary bioassay showed that the inhibitory rates against Monilia albican and Escherichia coli of N-[(1-aryl-3-phenyl-pyrazol-4-yl)methylene]-2-hydroxybenzohydrazide and 1-(2-hydroxybenzoyl)-3-methyl-4-substituted phenylhydrazono-pyrazolone compounds were high to 100 % at 0.01% mass concentration, which displayed excellent antibacterial activities. The inhibitory rates against Staphlococcus aureus were over 70%, which exhibited a certain extent antibacterial activities. inhibitory rates against Escherichia coli ofII series compounds(II3b、II3c) were high to 100 % at 0.01% mass concentration, which displayed excellent antibacterial activities. The inhibitory rates against Monilia albican and Staphlococcus aureus were over 70%, which exhibited a certain extent antibacterial activities.
The analysis of structure–activity relationships showed that the antibacterial activities of compounds were reduced by electron-donating and electron-withdrawing groups of the phenyl ring, such as -OCH_3、-NO_2、-CH_3. The antibacterial activities of compounds with -OCH_3 and -CH_3 is lower than compounds with the -NO_2. the antibacterial activities of compounds were enhanced by the halogen groups of the phenyl ring, and the antibacterial activities of p-substitued compounds is higher than 0-substitued. Furthermore, the antibacterial activities of the compounds II3a-II3f、III4a-III4f were significantly different. Compared with compounds II3a-II3f, the antibacterial activities of III4a-III4f were significantly enhanced.
以芳胺为原料,经重氮化、还原、与苯乙酮缩合、Vilsmeier-Haack反应,制得1-芳基-3-苯基-4-甲酰基吡唑,再与水杨酰肼反应制得N-[(1-芳基-3-苯基-吡唑-4-基)次甲基]-2-羟基苯甲酰肼(I4a-I4f),对制备中间体1-芳基-3-苯基-4-甲酰基吡唑(I3a-I3f)的反应机理进行验证和推理,揭示了闭环反应与1位芳环上取代基电子效应之间的关系规律。
以芳胺为原料,经重氮化、与乙酰乙酸乙酯反应,再与水杨酰肼缩合,制得2-取代苯腙基-3-(2-羟基苯甲酰腙基)-丁酸乙酯(II3a-II3f),经分子内闭环制得1-(2-羟基苯甲酰基)-3-甲基-4-取代苯腙基-吡唑啉酮化合物(III4a-III4f),探讨了制备目标化合物的反应机理,研究表明,介质的酸碱性对II3a-II3f、III4a-III4f的制备有显著影响,酸性介质中,反应难以停留在3a~3f阶段,而是快速闭环生成化合物III4a-III4f,要制备高收率的席夫碱II3a-II3f,反应介质需要控制在中性或弱碱性,制备化合物III4a-III4f最好控制在酸性介质中。
测试表明:质量浓度为0.01%时,N-[(1-芳基-3-苯基-吡唑-4-基)次甲基]-2-羟基苯甲酰肼系列化合物、1-(2-羟基苯甲酰基)-3-甲基-4-取代苯腙基-吡唑啉酮系列化合物对大肠杆菌、白色念珠菌的抑菌率均接近或高达100%,有极强的抑菌活性,对金黄色葡萄球菌的抑菌率均达70%以上,有一定的抑菌活性;2-取代苯腙基-3-(2-羟基苯甲酰腙基)-丁酸乙酯(II3b、II3c)对大肠杆菌的抑菌率高达100%,有极强的抑菌活性,对白色念珠菌、金黄色葡萄球菌的抑菌率均达70%以上,有一定的抑菌活性。
构效关系表明:三类化合物的抑菌活性均与芳环上的取代基性质有关,苯环中引入-OCH_3、-NO_2、-CH_3、导致化合物抑菌活性降低,且引入-OCH_3、-CH_3、的化合物较-NO_2的抑菌活性更低;苯环中引入Cl、Br等卤素原子,可显著提高化合物的抑菌活性,且对位引入卤原子的化合物均较间位的抑菌活性更佳。此外,关环前后II3a-II3f、III4a-III4f的抑菌活性有显著变化,与关环前系列化合物II3a~II3f相比,形成吡唑啉酮环后的化合物III4a-III4f的抑菌活性普遍显著提高。
Eighteen compounds were designed and synthesized by combining o-hydroxyl pheny、pyrazole and phenylhydrazone group, according to the superposition principle of biological activities. Twelve compounds and antibacterial-activity of eighteen compounds have not been reported so far. The structures of all compounds were confirmed by 1H NMR、IR and elemental analysis.
Substituted aniline was diazotized and subsequently reduced to give substituted phenylhydrazine, acetophenone arylhydrazone were obtained by the condensation of acetophenone with substituted phenylhydrazine, reacted with N,N-dimethylformamide、phosphorus oxychloride, l-aryl-3-phenyl-4-formylpyrazoles were obtained. Then reacted with salicylic hydrazide to obtain N-[(1-aryl-3-phenyl-pyrazol-4-yl)methylene]-2-hydroxybenzohydrazide (I4a-I4f), verified and deduced the reaction mechanism of acquiring the1-aryl-3-phenyl-4-formyl-pyrazoles(I3a-I3f), revealed the realationships between cyclization reaction activities and electronic effect of the 1- phenyl ring substituent.
Substituted aniline was diazotized and subsequently reacted with ethylacetoacetate, then condensed with salicylic hydrazide to obtain 3-(2-hydroxybenzoylhydrazono)-2-(2-phenylhydrazono)-ethyl butanoates(II3a-II3f). 1-(2-Hydroxybenzoyl)-3-methyl-4-substitued phenylhydrazono-pyrazolones(III4a-III4f) were acquired by intramolecular cyclization reaction of compounds II3a-II3f. The reaction mechanism of acquireing target compounds showed compounds II3a-II3f were difficult to maintain in acidic medium, but generated compounds III4a-III4f with rapid cyclization. So, preparation of compounds II3a-II3f should be in neutral or weak alkaline solution, but preparation of compounds II3a-II3f had better be in the acdic medium.
The result of preliminary bioassay showed that the inhibitory rates against Monilia albican and Escherichia coli of N-[(1-aryl-3-phenyl-pyrazol-4-yl)methylene]-2-hydroxybenzohydrazide and 1-(2-hydroxybenzoyl)-3-methyl-4-substituted phenylhydrazono-pyrazolone compounds were high to 100 % at 0.01% mass concentration, which displayed excellent antibacterial activities. The inhibitory rates against Staphlococcus aureus were over 70%, which exhibited a certain extent antibacterial activities. inhibitory rates against Escherichia coli ofII series compounds(II3b、II3c) were high to 100 % at 0.01% mass concentration, which displayed excellent antibacterial activities. The inhibitory rates against Monilia albican and Staphlococcus aureus were over 70%, which exhibited a certain extent antibacterial activities.
The analysis of structure–activity relationships showed that the antibacterial activities of compounds were reduced by electron-donating and electron-withdrawing groups of the phenyl ring, such as -OCH_3、-NO_2、-CH_3. The antibacterial activities of compounds with -OCH_3 and -CH_3 is lower than compounds with the -NO_2. the antibacterial activities of compounds were enhanced by the halogen groups of the phenyl ring, and the antibacterial activities of p-substitued compounds is higher than 0-substitued. Furthermore, the antibacterial activities of the compounds II3a-II3f、III4a-III4f were significantly different. Compared with compounds II3a-II3f, the antibacterial activities of III4a-III4f were significantly enhanced.
引文
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