新型氮唑类化合物的合成及抗真菌活性研究

柯学峰; 李京哲; 付奔; 李良景; 柴晓云; 吴秋业

doi:10.3969/j.issn.1006-0111.2017.01.006

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新型氮唑类化合物的合成及抗真菌活性研究

柯学峰, 李京哲, 付奔, 李良景, 柴晓云, 吴秋业

文章导航 > 药学实践与服务 > 2017 > 35(1): 22-25,59

柯学峰, 李京哲, 付奔, 李良景, 柴晓云, 吴秋业. 新型氮唑类化合物的合成及抗真菌活性研究[J]. 药学实践与服务, 2017, 35(1): 22-25,59. doi: 10.3969/j.issn.1006-0111.2017.01.006

引用本文:

KE Xuefeng, LI Jingzhe, FU Ben, LI Liangjing, CHAI Xiaoyun, WU Qiuye. Synthesis and antifungal activity of the novel azole compounds[J]. Journal of Pharmaceutical Practice and Service, 2017, 35(1): 22-25,59. doi: 10.3969/j.issn.1006-0111.2017.01.006

Citation:

KE Xuefeng, LI Jingzhe, FU Ben, LI Liangjing, CHAI Xiaoyun, WU Qiuye. Synthesis and antifungal activity of the novel azole compounds[J]. Journal of Pharmaceutical Practice and Service, 2017, 35(1): 22-25,59. doi: 10.3969/j.issn.1006-0111.2017.01.006

新型氮唑类化合物的合成及抗真菌活性研究

doi: 10.3969/j.issn.1006-0111.2017.01.006

1.
第二军医大学药学院有机化学教研室, 上海 200433
2.
第二军医大学药学院有机化学教研室, 上海 200433;第二军医大学临床医学五年制学员旅学员十队, 上海 200433

基金项目: 国家自然科学基金（20972188），上海科委重点攻关课题（09dZ1976700）

Synthesis and antifungal activity of the novel azole compounds

1.
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
2.
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China;Cadet Company 10 th, Student Brigade, Second Military Medical University, Shanghai 200433, China

摘要: 目的设计合成含有1，3，4-二唑侧链的新型氮唑类化合物，并研究其体外抗真菌活性。方法通过酰化、胺解、环合、亲核取代等多步反应合成了14个未见文献报道的目标化合物，其结构通过¹H NMR、MS确证，选择6种真菌为实验菌株，用微量液体稀释法检测目标化合物的体外抑菌活性。结果所有目标化合物对实验菌株均有一定的抑制活性，尤其对白念珠菌活性较好。化合物 10d 、 10i 、 10l 、 10n 对白念珠菌的MIC₈₀值为0.003 9 μg/ml，是伊曲康唑（MIC₈₀：0.062 5 μg/ml）的16倍，是氟康唑（MIC₈₀：0.25 μg/ml）的64倍。结论 1，3，4-二唑侧链结构的引入对化合物的活性有影响，可能是侧链结构中二唑环与苯环能够与靶酶较好地结合，从而提高了化合物的活性。
- 1,3,4-二唑 /
- 合成 /
- 抗真菌活性
Abstract: Objective To design and synthesize novel triazole antifungal derivatives with 1,3,4-oxadiazole side chain for the study of antifungal activities. Methods Fourteen title compounds were synthesized via acylation, aminolysis reaction, cyclization, nucleophilic substitution, etc. All the compounds were characterized by ¹H NMR, MS spectra. The in vitro antifungal activities were evaluated against six human pathogenic fungi through the micro-broth dilution method. Results The title compounds exhibited strong antifungal activities against all the tested fungi, especially against Candida albicans. Compounds 10d , 10i , 10l , and 10n were found to be the most effective, with a minimum inhibitory concentration(MIC₈₀) of 0.003 9 μg/ml.They are 16-fold more potent than ICZ (MIC₈₀ 0.062 5 μg/ml) and 64-fold more potent than FCZ (MIC₈₀ 0.25 μg/ml). Conclusion The 1,3,4-oxadiazole side chain could affect the antifungal activities. That could be due to the proper incorporation between the 1,3,4-oxadiazole substituted phenyl ring with the target enzyme.
- azole /
- 1,3,4-oxadiazole /
- synthesis

[1]	Nuccil M, Marr KA. Emerging fungal diseases[J]. Clin Infect Dis, 2005, 41(4):521-526.[2] Boschman CR, Bodnar UR, Tornatore MA, et al. Thirteen-year evolution of azole resistance in yeast isolates and prevalence of resistant strains carried by cancer patients at a large medical center[J]. Antimicrob Agents Chemother, 1998, 42(4):734-738.[3] 冷萍,郭秀丽,娄红祥.真菌耐药的分子机制及新型抗真菌药物[J].生理科学进展, 2005, 36(4):325-328.[4] Koltin Y, Hitchcock CA. Progress in the search for new triazole antifungal agents[J]. Curr Opin Chem Biol, 1997, 1(2):176-182.[5] Gallis HA, Drew RH, Pickard WW. Amphotericin B:30 years of clinical experience[J]. Rev Infect Dis,1990, 12(2):308-329.[6] Gallis HA. Amphotercin B:a commentary on its role as an antifungal agent and as a comparative agent in clinical trials[J]. Clin Infect Dis, 1996, 22(Suppl 2):S145-S147.[7] Li LJ, Ding H, Wang BG, et al. Synthesis and evaluation of novel azoles as potent antifungal agents[J]. Bioorg Med Chem Lett, 2014, 24(1):192-194.[8] National Committee for Clinical Laboratory Standards, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts Approved standard[S]. Document M27-A2, National Committee for Clinical Laboratory Standards, Wayne, PA, 2002.[9] Chai XY, Zhang J, Hu HG, et al.Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P45014α-demethylase[J]. Eur J Med Chem, 2009, 44(5):1913-1920.
[2]	Chai XY, Zhang J, Yu SC, et al. Design, synthesis, and biological evaluation of novel 1-(1H-1,2,4-triazole-1-yl)-2- (2,4-difluorophenyl)-3-substituted benzylamino-2-propanols[J]. Bioorg Med Chem Lett, 2009, 19(6):1811-1814.
[3]	Chai XY, Zhang J, Cao YB, et al.Design, synthesis and molecular docking studies of novel triazole as antifungal agent[J]. Eur J Med Chem, 2011, 46(7):3167-3176.
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[6]	Zou Y, Yu SC, Li RW, et al. Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4-difluorophenyl) -2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates[J]. Eur J Med Chem, 2014, 74(4):366-374.

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新型氮唑类化合物的合成及抗真菌活性研究

doi: 10.3969/j.issn.1006-0111.2017.01.006

1. 第二军医大学药学院有机化学教研室, 上海 200433

2. 第二军医大学药学院有机化学教研室, 上海 200433;第二军医大学临床医学五年制学员旅学员十队, 上海 200433

基金项目: 国家自然科学基金（20972188），上海科委重点攻关课题（09dZ1976700）

收稿日期: 2016-11-10
修回日期: 2016-12-21

关键词:

1,3,4-二唑 /

合成 /

抗真菌活性

摘要: 目的设计合成含有1，3，4-二唑侧链的新型氮唑类化合物，并研究其体外抗真菌活性。方法通过酰化、胺解、环合、亲核取代等多步反应合成了14个未见文献报道的目标化合物，其结构通过¹H NMR、MS确证，选择6种真菌为实验菌株，用微量液体稀释法检测目标化合物的体外抑菌活性。结果所有目标化合物对实验菌株均有一定的抑制活性，尤其对白念珠菌活性较好。化合物 10d 、 10i 、 10l 、 10n 对白念珠菌的MIC₈₀值为0.003 9 μg/ml，是伊曲康唑（MIC₈₀：0.062 5 μg/ml）的16倍，是氟康唑（MIC₈₀：0.25 μg/ml）的64倍。结论 1，3，4-二唑侧链结构的引入对化合物的活性有影响，可能是侧链结构中二唑环与苯环能够与靶酶较好地结合，从而提高了化合物的活性。

English Abstract

Synthesis and antifungal activity of the novel azole compounds

1. Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

2. Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China;Cadet Company 10 th, Student Brigade, Second Military Medical University, Shanghai 200433, China

Received Date: 2016-11-10
Rev Recd Date: 2016-12-21

Keywords:

azole /
1,3,4-oxadiazole /
synthesis

Abstract: Objective To design and synthesize novel triazole antifungal derivatives with 1,3,4-oxadiazole side chain for the study of antifungal activities. Methods Fourteen title compounds were synthesized via acylation, aminolysis reaction, cyclization, nucleophilic substitution, etc. All the compounds were characterized by ¹H NMR, MS spectra. The in vitro antifungal activities were evaluated against six human pathogenic fungi through the micro-broth dilution method. Results The title compounds exhibited strong antifungal activities against all the tested fungi, especially against Candida albicans. Compounds 10d , 10i , 10l , and 10n were found to be the most effective, with a minimum inhibitory concentration(MIC₈₀) of 0.003 9 μg/ml.They are 16-fold more potent than ICZ (MIC₈₀ 0.062 5 μg/ml) and 64-fold more potent than FCZ (MIC₈₀ 0.25 μg/ml). Conclusion The 1,3,4-oxadiazole side chain could affect the antifungal activities. That could be due to the proper incorporation between the 1,3,4-oxadiazole substituted phenyl ring with the target enzyme.