三唑类新化合物的设计合成及抗真菌和抗细菌活性研究
摘要
1,2,4-三唑是一种重要的含氮五元杂环化合物,分子内含有三个氮原子和π-π共轭体系,具有较强的络合金属离子和形成氢键的能力,这种独特结构性质使三唑类化合物表现出广谱的生物活性及某些特殊性能,不仅在医药和农药领域得到了广泛应用,同时在超分子化学、材料科学、生命科学等领域具有潜在的开发价值。本论文根据三唑类化合物抗菌、抗真菌的国内外研究与开发现状,设计合成了一系列单三唑醚、双三唑醚、双三唑及双三唑鎓类化合物,并初步研究了它们的体外抗真菌和抗细菌活性,讨论了化合物的结构与抗微生物活性的关系。主要工作总结如下：
(1)单三唑醚类化合物的合成：以苯肼为原料,经环化合成中间体苯基三唑醇81,与苄基卤化物或卤代烷烃通过亲核取代制得卤苄基和烷基单三唑醚83-84及其盐酸盐衍生物85-86。
(2)双三唑类化合物的合成：以1,2,4-三唑和环氧氯丙烷为起始原料制得双三唑90-91和双三唑鎓93。三唑酮87经溴化后得到溴化物88,与苯基三唑醇或苄基三唑硫醇反应得到双三唑类化合物90a-b,进而经NaBH4还原得到目标化合物91a-b；1,2,4-三唑与环氧氯丙烷反应制得双三唑醇92,随后中间体92经三唑N-季铵化,得到双三唑鎓类化合物93a-d。
(3)双三唑醚类化合物的合成：以环氧氯丙烷为原料,与苯基三唑醇81反应得双三唑醚94,进而与苄基卤化物反应得到卤苄双三唑醚95；苯基三唑醇81与二溴化物反应制得烷基双三唑醚96及其盐酸盐97。
(4)探索了环氧氯丙烷与苯基三唑醇的开环反应条件,得出了中间体双苯基三唑醇94合成的适宜条件；探讨了制备α-溴代三唑酮88的反应条件,发现投料比例和反应时间对目标物的产率具有重要影响。
(5)合成的新化合物结构均通过IR、NMR和MS谱确证。
(6)体外抗细菌、抗真菌研究表明所合成的卤苄三唑醚、烷基三唑醚、卤苄双三唑醚、烷基双三唑醚类化合物对所测试的细菌、真菌具有较弱的抑制活性,而其相应的盐酸盐显示相对较好的抑制作用,其中含2,4-二氟苄醚三唑化合物82b及其盐酸盐84b对铜绿杆菌和大肠杆菌显示最有效的抑制活性,最小抑制浓度分别为112.5μM和56.2μM。三唑鎓系列化合物均显示出有效的、广谱的抑菌活性,其中2,4-二氟、2,4-二氯苄基取代化合物93a和93b活性最佳,其对所测试菌种的MIC值为13.2μM-52.6μM,优于临床使用的对照药物氯霉素,值得进一步研究开发。初步的构效关系研究表明,苯环上取代基类型、卤原子取代个数及位次对抗菌活性有一定程度的影响,烷基链的长度对抗菌活性有重要影响。此外,化合物的水溶性对其生物活性有一定影响。
本论文共合成53个化合物,其中新化合物48个,包括卤苄三唑醚16个,烷基三唑醚类14个,卤苄双三唑醚4个,烷基双三唑醚6个,双三唑类化合物4个,双三唑鎓衍生物4个。
1,2,4-Triazole is a nitrogen-containing aromatic heterocyclic scaffold of paramount importance, contains three nitrogens andπ-πconjugated system, has strong coordination capability and is easy to form hydrogen bonds.This unique structural nature of 1,2,4-triazoles grants their broad spectrum of biological activities and some other special properties, not only widely used in medicine and agriculture, but having huge exploitation valuel in supramolecular chemistry, material science, life science and so on. This thesis based on the current situation of triazoles as antifungal and antibacterial agents, designed and synthesized a series of triazole ethers, bis-triazole ethers, bis-triazole and bis-triazolium compounds, and these synthesized new compounds were evaluated for their antimicrobial activities. The preliminary structure-activity relationships were also discussed. The main work was summarized as follows:
(1)Synthesis of triazolyl ethers:The target halobenzyl triazolyl ether 83 and alkyl triazolyl ether 84, including their corresponding hydrochlorides 85 and 86 were prepared starting from phenylhydrazine via the reaction of cyclization, nucleophilic substitution reaction of phenyl triazol-3-ol 81 with a series of aryl halides and alkyl halides.
(2) Synthesis of bis-triazoles:The target bis-triazoles 90-91 and bis-triazolium 93 were prepared starting from 1,2,4-triazole and epichlorohydrin. Triazodone 87 was brominated by bromine to afford the corresponding bromide 88, and then the later 88 reacted with phenyltriazol-3-ol or benzyltriazol-3-thiol to give the desired bis-triazole 90.Compounds 90a-b were reduced by NaBH4 to produce the corresponding alcohols 91a-b. The N-alkylation of 1,2,4-triazole with epichlorohydrin yielded bis-triazole propanol 92,and compound 92 was quaternized with a series of halobenzyl chlorides or bromides to give the desired bis-triazolium compounds 93a-d.
(3)Synthesis of bis-triazolyl ethers:The target halobenzyl bis-triazolyl ether 95 was obtained by the reaction of epichlorohydrin with phenyl triazol-3-ol 81 and then with a series of aryl halides. Alkyl bis-triazolyl ether 96 including its corresponding hydrochloride 97 was prepared via the etherization of phenyl triazol-3-ol 81 with a series of dibromides.
(4) The reaction conditions for the opening ring of epichlorohydrin with phenyl triazole-3-ol 81 were investigated, and good condition for the synthesis of intermediate 94 was obtained. The preparation of compound 88 was also explored and the results exhibited that the feeding ratio and reaction time have significant effect on the yields of target compound.
(5) The newly synthesized compounds were confirmed by IR, NMR and MS spectra.
(6) The antibacterial and antifungal assays in vitro showed that the synthesized novel halobenzyl triazole ethers, alkyl triazole ethers, halobenzyl bis-triazole ethers, alkyl bis-triazole ethers displayed weak activities against tested bacteria and fungi, while their corresponding hydrochlorides exhibited better antimicrobial efficacy. Among these series, compound 82b containing difluorobenzyl moiety and its hydrochloride 84b showed the best activity against P. aeruginosa and E. coli with the MIC values of 112.5μM and 56.2μM respectively. However, bis-triazoliums displayed significant and widespread inhibitory activity against most of the tested strains.Compounds 93a and 93b carrying difluorobenzyl and dichlorobenzyl groups in the triazolium ring were the most potential compounds against some tested strains with the MIC values ranging from 13.2μM to 52.6μM, and exhibited much stronger activities than reference drug chloramphenicol in clinic. It is well worth further researching and developing this kind of compounds as antibacterial agents.The structure-activity relationships showed that the type of substitutents, the number and location of the halogen atom in the aryl ring and the length of alkyl chain are responsible for the variation of the antibacterial and antifungal activities. Moreover, the water-solubility of the tested compounds also exhibited significant effect on their biological atcivities.
Fifty three compounds were successfully synthesized in this thesis, including sixteen halobenzyl triazolyl ethers, fourteen alkyl triazolyl ethers, four halobenzyl bis-triazolyl ethers, six alkyl bis-triazolyl ethers, four bis-triazole compounds and four bis-triazolium compounds. Among these synthesized compounds, forty eight triazole derivatives were new.
(1)单三唑醚类化合物的合成：以苯肼为原料,经环化合成中间体苯基三唑醇81,与苄基卤化物或卤代烷烃通过亲核取代制得卤苄基和烷基单三唑醚83-84及其盐酸盐衍生物85-86。
(2)双三唑类化合物的合成：以1,2,4-三唑和环氧氯丙烷为起始原料制得双三唑90-91和双三唑鎓93。三唑酮87经溴化后得到溴化物88,与苯基三唑醇或苄基三唑硫醇反应得到双三唑类化合物90a-b,进而经NaBH4还原得到目标化合物91a-b；1,2,4-三唑与环氧氯丙烷反应制得双三唑醇92,随后中间体92经三唑N-季铵化,得到双三唑鎓类化合物93a-d。
(3)双三唑醚类化合物的合成：以环氧氯丙烷为原料,与苯基三唑醇81反应得双三唑醚94,进而与苄基卤化物反应得到卤苄双三唑醚95；苯基三唑醇81与二溴化物反应制得烷基双三唑醚96及其盐酸盐97。
(4)探索了环氧氯丙烷与苯基三唑醇的开环反应条件,得出了中间体双苯基三唑醇94合成的适宜条件；探讨了制备α-溴代三唑酮88的反应条件,发现投料比例和反应时间对目标物的产率具有重要影响。
(5)合成的新化合物结构均通过IR、NMR和MS谱确证。
(6)体外抗细菌、抗真菌研究表明所合成的卤苄三唑醚、烷基三唑醚、卤苄双三唑醚、烷基双三唑醚类化合物对所测试的细菌、真菌具有较弱的抑制活性,而其相应的盐酸盐显示相对较好的抑制作用,其中含2,4-二氟苄醚三唑化合物82b及其盐酸盐84b对铜绿杆菌和大肠杆菌显示最有效的抑制活性,最小抑制浓度分别为112.5μM和56.2μM。三唑鎓系列化合物均显示出有效的、广谱的抑菌活性,其中2,4-二氟、2,4-二氯苄基取代化合物93a和93b活性最佳,其对所测试菌种的MIC值为13.2μM-52.6μM,优于临床使用的对照药物氯霉素,值得进一步研究开发。初步的构效关系研究表明,苯环上取代基类型、卤原子取代个数及位次对抗菌活性有一定程度的影响,烷基链的长度对抗菌活性有重要影响。此外,化合物的水溶性对其生物活性有一定影响。
本论文共合成53个化合物,其中新化合物48个,包括卤苄三唑醚16个,烷基三唑醚类14个,卤苄双三唑醚4个,烷基双三唑醚6个,双三唑类化合物4个,双三唑鎓衍生物4个。
1,2,4-Triazole is a nitrogen-containing aromatic heterocyclic scaffold of paramount importance, contains three nitrogens andπ-πconjugated system, has strong coordination capability and is easy to form hydrogen bonds.This unique structural nature of 1,2,4-triazoles grants their broad spectrum of biological activities and some other special properties, not only widely used in medicine and agriculture, but having huge exploitation valuel in supramolecular chemistry, material science, life science and so on. This thesis based on the current situation of triazoles as antifungal and antibacterial agents, designed and synthesized a series of triazole ethers, bis-triazole ethers, bis-triazole and bis-triazolium compounds, and these synthesized new compounds were evaluated for their antimicrobial activities. The preliminary structure-activity relationships were also discussed. The main work was summarized as follows:
(1)Synthesis of triazolyl ethers:The target halobenzyl triazolyl ether 83 and alkyl triazolyl ether 84, including their corresponding hydrochlorides 85 and 86 were prepared starting from phenylhydrazine via the reaction of cyclization, nucleophilic substitution reaction of phenyl triazol-3-ol 81 with a series of aryl halides and alkyl halides.
(2) Synthesis of bis-triazoles:The target bis-triazoles 90-91 and bis-triazolium 93 were prepared starting from 1,2,4-triazole and epichlorohydrin. Triazodone 87 was brominated by bromine to afford the corresponding bromide 88, and then the later 88 reacted with phenyltriazol-3-ol or benzyltriazol-3-thiol to give the desired bis-triazole 90.Compounds 90a-b were reduced by NaBH4 to produce the corresponding alcohols 91a-b. The N-alkylation of 1,2,4-triazole with epichlorohydrin yielded bis-triazole propanol 92,and compound 92 was quaternized with a series of halobenzyl chlorides or bromides to give the desired bis-triazolium compounds 93a-d.
(3)Synthesis of bis-triazolyl ethers:The target halobenzyl bis-triazolyl ether 95 was obtained by the reaction of epichlorohydrin with phenyl triazol-3-ol 81 and then with a series of aryl halides. Alkyl bis-triazolyl ether 96 including its corresponding hydrochloride 97 was prepared via the etherization of phenyl triazol-3-ol 81 with a series of dibromides.
(4) The reaction conditions for the opening ring of epichlorohydrin with phenyl triazole-3-ol 81 were investigated, and good condition for the synthesis of intermediate 94 was obtained. The preparation of compound 88 was also explored and the results exhibited that the feeding ratio and reaction time have significant effect on the yields of target compound.
(5) The newly synthesized compounds were confirmed by IR, NMR and MS spectra.
(6) The antibacterial and antifungal assays in vitro showed that the synthesized novel halobenzyl triazole ethers, alkyl triazole ethers, halobenzyl bis-triazole ethers, alkyl bis-triazole ethers displayed weak activities against tested bacteria and fungi, while their corresponding hydrochlorides exhibited better antimicrobial efficacy. Among these series, compound 82b containing difluorobenzyl moiety and its hydrochloride 84b showed the best activity against P. aeruginosa and E. coli with the MIC values of 112.5μM and 56.2μM respectively. However, bis-triazoliums displayed significant and widespread inhibitory activity against most of the tested strains.Compounds 93a and 93b carrying difluorobenzyl and dichlorobenzyl groups in the triazolium ring were the most potential compounds against some tested strains with the MIC values ranging from 13.2μM to 52.6μM, and exhibited much stronger activities than reference drug chloramphenicol in clinic. It is well worth further researching and developing this kind of compounds as antibacterial agents.The structure-activity relationships showed that the type of substitutents, the number and location of the halogen atom in the aryl ring and the length of alkyl chain are responsible for the variation of the antibacterial and antifungal activities. Moreover, the water-solubility of the tested compounds also exhibited significant effect on their biological atcivities.
Fifty three compounds were successfully synthesized in this thesis, including sixteen halobenzyl triazolyl ethers, fourteen alkyl triazolyl ethers, four halobenzyl bis-triazolyl ethers, six alkyl bis-triazolyl ethers, four bis-triazole compounds and four bis-triazolium compounds. Among these synthesized compounds, forty eight triazole derivatives were new.
引文
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