【作者】 米佳丽；

【导师】 周成合；

【作者基本信息】 重庆医科大学 ， 药物化学， 2008， 硕士

【摘要】 三唑类抗微生物药物已成为新药研究与开发的热点领域之一。本论文根据三唑类抗微生物药物的国内外研发现状,以市售的2′,4′-二氟-2-(1H-1,2,4-三唑-1-基)苯乙酮18为原料,经过还原、醚化、季铵化等多步反应,设计合成了一系列新型醚类和胺类氟三唑化合物,初步研究了它们的体外抗微生物活性,并探讨了一些反应条件以及化合物的结构与抗微生物活性的关系。新型醚类氟三唑的合成以三唑酮18为原料,经硼氢化钠还原得到三唑醇中间体19,三唑醇19分别与一系列单卤代物反应合成了一系列新型脂肪醚类氟三唑20;与双卤代物得到一系列新型卤代烷基醚类氟三唑22;与卤代苄卤化合物反应得到一系列新型卤代苄醚类氟三唑24。氟三唑20、22、24分别与硝酸反应制得了其相应的硝酸盐21、23、25;化合物24与卤代苄卤化合物季铵化反应得到氟三唑鎓衍生物26。新型胺类氟三唑的合成以硝基化合物24g为原料,在钯炭/氢气条件下还原合成了氨类氟三唑27。氨基氟三唑27与一系列卤代苄卤化合物氨化得对应氟三唑的仲胺28和叔胺29衍生物。改进了硼氢化钠还原三唑酮18的反应条件,提高了目标物的产率。同时,探讨了三唑醇19、氟三唑胺27分别与卤代物反应条件,其中温度、浓度和卤代物的活泼程度对目标物产率具有重要影响。合成的新化合物结构均通过IR、1H NMR、13C NMR、MS确证。体外抗微生物研究表明,所合成的氟三唑类化合物对所测真菌具有显著的抑制活性,部分化合物也具有明显的抗菌活性。其中,化合物24a、24d、24e、25a、25d、29a、29b对白色念珠菌具有很强的抑制作用,其活性优于临床药物氟康唑;化合物21b、25a、25c、28a对烟曲霉菌具有较好的抑制作用;化合物21d、29b对金黄色葡萄球菌的抑制活性优于抗菌药氯霉素,与喹诺酮类抗生素诺氟沙星相当;化合物21b、28d、29b显示了显著的抑制铜绿假单胞菌的活性,优于氯霉素,与诺氟沙星相当;化合物21b、25d、29b具有明显的抑制枯草杆菌活性,相当于氯霉素和诺氟沙星;化合物24e、28c、28d对变形杆菌的抑制活性优于对照药物氯霉素和诺氟沙星;化合物21a、21b对大肠杆菌的抑制活性较强,相当于诺氟沙星。这些化合物值得进一步研究开发。构效关系研究表明,苯环上卤素取代抗真菌活性显著,而且卤素的取代位置对抗真菌活性影响较大;短链的脂肪烃比长链类活性显著;脂肪烃末端被卤素取代,活性比未取代显著;季铵盐衍生物活性更佳;氨基双取代的叔胺衍生物抗微生物活性优于仲胺衍生物。本论文共合成40个化合物,其中新化合物39个,包括氟三唑16个,氟三唑硝酸盐15个,氟三唑鎓 1个,氟三唑胺8个。更多还原

【Abstract】 Research and development of triazoles as antimicrobial agents have become one of active fields in medicinal chemistry. This thesis based on the current situation of triazoles as antifungal and antibacterial agents, designed and synthesized a series of novel ether and amino fluorotriazoles by reduction, etherization, and quaternization and so on starting from commercial 1-(2,4-difluoro phenyl)-2-(1H-1,2,4-triazol-1-yl) ethanone 18, and evaluated in vitro for the antifungal and antibacterial activities of the new synthetic compounds. Some reaction conditions and structure-activity relationships were also discussed.The synthesis of novel ether fluorotriazoles started from commercial triazolone 18. The later was reduced with sodium borohydride to afford the triazolyl alcohol 19 in high yield. Then the intermediate 19 reacted with respectively a series of alkyl halides to afford the desired aliphatic ether fluorotriazole 20, alkyl dihalides to give the haloalkyl fluorotriazole 22, halobenzyl halides to yield aralkyl fluorotriazole 24. The fluorotriazoles 20, 22 and 24 were treated by nitrate acid to afford the corresponding nitrate salts 21, 23 and 25. The ether fluorotriazole 24 was quaternized by halobenzyl halides to give the desired fluorotriazolium 26. The desired novel amino fluorotriazoles were prepared from the nitro compound 24g. The catalytic hydrogenation of nitro fluorotriazole 24g in methanol using Pd/C as catalyst gave amino fluorotriazole 27. Compound 27 was condensed with a series of halobenzyl halides to afford the desired amino compounds 28 and 29 respectively. All the synthetic new compounds were confirmed by IR, 1H NMR, 13C NMR and/or MS.The reduction condition of triazolone 18 was improved and the target compound 19 was obtained successfully in higher yield. The reaction conditions of halides with respectively triazolyl alcohol 19 and fluorotriazole amine 27 were explored, and the results showed that the temperature, halide and its concentration were three important factors for the synthesis of target compounds.The antimicrobial activities in vitro showed that all the synthetic new fluorotriazoles displayed potent activities against fungi. Some fluorotriazoles also showed good activity against bacteria. Especially, compounds 24a, 24d, 24e, 25a, 25d, 29a and 29b showed better activity against C.albicans than fluconazole which is being used in clinic. Among tested compounds, fluorotriazole 21b, 25a, 25c and 28a showed the strongest activity against A.fumigatus. Compounds 21d and 29b had better activity against S.aureus than amphemycin using in clinic and get close to the norfloxacin. Compounds 21b, 28d and 29b also showed better activity against P.aeruginosa than amphemycin and get close to the norfloxacin. Compounds 21b, 25d and 29b gave stronger activity against B. subtilis than amphemycin and get close to the norfloxacin. Compounds 24e, 28c and 28d gave stronger activity against B.proteus than amphemycin and get close to the norfloxacin. Compounds 21a and 21b showed better activity against E.coli than amphemycin and get close to the norfloxacin. These compounds are promising for further research and development as antimicrobial agents.The structure-activity relationships showed that haloaryl fluorotriazoles had the better antimicrobial activities than other groups, and the position of halogen atoms in aryl ring possess important to antimicrobial activities; the fluorotriazoles with short alkyl chain gave better activities than long ones; haloalkyl fluorotriazoles had stronger activies than non-haloalkyl derivatives. The fluorotriazoliums possess good stability and gave better antimicrobial activies. The secondary amine-type fluorotriazoles displayed lower activities than tertiary amine-type derivatives.In this thesis, 40 Compounds were successfully synthesized. Among these synthetic compounds 39 fluorotriazole derivatives were new, including 16 fluorotriazoles, 15 fluorotriazole nitrate salts, 1 fluorotriazolium, and 8 amino fluorotriazoles.更多还原