【作者】 袁勇；

【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】 唑类抗微生物药物已经成为新药研究与开发的热点领域之一。本文根据咪唑、苯并咪唑类抗微生物药物的国内外研发现状,选择市售的咪唑、苯并咪唑为原料,经过N-烷化、季铵化等多步反应,设计合成了一系列新型双咪唑、双苯并咪唑等双唑类化合物,并研究了其体外抗微生物活性。新型双咪唑类化合物包括烷基、芳烷基双咪唑鎓类和卤苄叔胺双咪唑类两个系列。双咪唑鎓类化合物的合成以咪唑为原料,在NaH作用下,以THF为溶剂,反应生成单咪唑钠盐,与卤代苄氯反应生成卤代苄基咪唑中间体(21a ~ 21c),再与烷基、芳烷基二溴化合物在乙腈中季铵化反应,得到烷基、芳烷基双咪唑鎓类化合物(22a ~ 22b)。卤苄叔胺双咪唑类化合物以卤代苄氯为起始物,和二乙醇胺反应生成中间体(23a ~ 23d),再用PBr3溴化得到二溴化合物中间体(24a ~ 24d),之后与咪唑进行氮烷化反应生成卤苄叔胺双咪唑类目标化合物(25a ~ 25d)。新型双苯并咪唑类化合物的合成有两条路线。一条路线是以苯并咪唑为原料,在NaH作用下,生成单苯并咪唑钠盐,与取代苄氯反应生成卤代苄基苯并咪唑中间体(26a ~ 26c),之后与烷基、芳烷基二溴化合物在乙腈中进行季铵化反应生成双苯并咪唑鎓(27a ~ 27m)。另一途径为苯并咪唑在NaH作用下,在THF作为溶剂的条件下,反应生成单苯并咪唑钠盐,先与烷基、芳烷基二溴化合物反应生成双苯并咪唑(28a ~ 28b),之后再与卤代苄氯进行季铵化反应生成目标化合物双苯并咪唑鎓(27l ~ 27m)。所合成的化合物结构通过IR、MS、1H NMR和/或13C NMR谱确证。初步研究了目标分子双唑化合物及其一些中间体对两种真菌(烟曲霉菌、白色念珠菌)和五种细菌(变形杆菌、大肠杆菌、铜绿假单胞菌、枯草杆菌、金黄色葡萄球菌)的抗微生物活性,测试结果表明,合成的大部分化合物都具有一定的抗菌活性,部分中间体也具有一定的抗微生物活性,但其抗微生物活性明显低于目标化合物,其中化合物22a、27c、27e、27f、27k、27l和27m对某些细菌的活性比临床药物氯霉素和诺氟沙星强。抗真菌活性测试发现,所有目标化合物的抗真菌活性均低于临床抗真菌药氟康唑。其中对真菌和细菌均较好的为的双苯并咪唑类衍生物(27k、27l和27m)。部分化合物值得进一步研究。初步的构效关系表明:双唑鎓的抗菌活性比非双唑鎓好。通过芳烷基键连的双唑化合物比6个C原子及其以下的烷基键连的双唑化合物活性好。但10个C原子的烷基键连的化合物却表现出更好的抗菌活性。双苯并咪唑比双咪唑的抗菌活性更好,可能苯并咪唑比咪唑多了一个芳香苯环,能够更好地与细菌相互作用。邻氯、间氯和对氯的存在可以增强抗菌活性,2,4-二氟、3,4-二氯衍生物对某类细菌表现出抗菌活性增强,但是差别很小。本论文共合成化合物35个,包括中间体16个,双咪唑类化合物6个,双苯并咪唑类化合物13个,所得到的19个双唑类化合物均为新化合物。更多还原

【Abstract】 Research and development of azole antimicrobial agents have become one of hot area in medicinal chemistry. Based on the current investigative situation of azole agents, a series of novel bis-imidazole and bis-benzimidazole compounds as antibacterial and antifungal agents were designed, synthesized and evaluated for antimicrobial activities of these novel compounds in vitro in this thesis.Novel bis-azole compounds were divided into two parts: alkyl and aralkyl bis-imidazoliums and tertiary amine-type bis-imidazoles. Alkyl and aralkyl ones were prepared from commercial imidazole. The intermediate imidazole sodium, which was obtained by treatment of imidazole with NaH, reacted with halobenyl chloride to afford the mono-imidazoles (21a ~ 21c), and the laters reacted with a series of alkyl and aralkyl dibromides to yield the target bis-imidazolium compounds (22a ~ 22b). The tertiary amine-type bis-imidazoles were synthesized from substituted benzyl chloride as starting material. The reaction of halobenzyl chlorides with diethanolamine gave the diols (23a ~ 23d), then were brominated with PBr3 to afford the dibromides (24a ~ 24d), after that reacted with imidazole to yield the target bis-imidazole compounds (25a ~ 25d).Novel bis-benzimidazoles compounds could be prepared by two synthetic routes. One is to use benzimidazole as starting material, first to prepare benzimidazole sodium, and then react with substituted benzyl chloride to synthesize the mono-benzimidazole intermediates (26a ~ 26c), after that react with a series of alkyl and aralkyl dibromides to afford the target bis-benimidazolium compounds (27a ~ 27k). Another synthetic route is that benzimidazole first reacted with dibromide to prepare bis-benimidazole compounds (28a ~ 28b), then quaternized with substituted benzyl chloride to yield the target bis-benimidazoliums (27l ~ 27m).All the synthesized compounds were confirmed by IR, MS, 1H and/or 13C NMR spectra.The preliminary antimicrobial activities against 2 fungi (Aspergilus fumigatus、Candida albicans) and 5 bacteria (Bacilus proteus、Escherichia coli、Pseudomonas aeruginosa、Bacillus subtilis、Staphylococcus aureus) showed most of synthesized compounds among tested bis-azoles and their intermediates exhibit significant antibacterial activity. Compounds 22a, 27c, 27e, 27f, 27k, 27l and 27m) gave better activity against some bacteria than two reference drugs chloramphenicol and nofloxacin; all compounds showed less antifungal activities than the drug fluconazole in clinic. Among all compounds, bis-benzimidazole compound 27k showed best antimicrobial activities both fungi and bacteria.Bis-azoliums displayed better antibacterial activity than bis-azoles, and bis-benzimidazoles is better than bis-imidazoles for biological activity, possible reason is that benzimidaozle has one aromatic benzene ring, could help to interact between synthesized compounds and fungi or bacteria.Orth-chloro, meta-chloro and para-chloro benzyl group can help to strengthen antibacterial activities, 2,4-difluoro and 3,4-dichloro derivatives gave better activities , but the difference is very small.In this thesis, 35 compounds were synthesized, including 16 intermediates, 6 bis-imidazoles and 13 bis-benzimidazoles, all bis-azole compounds are new compounds.更多还原