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协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究

赵晶 李冉 代黎 蔡瞻 张大志 姜远英

赵晶, 李冉, 代黎, 蔡瞻, 张大志, 姜远英. 协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究[J]. 药学实践与服务, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
引用本文: 赵晶, 李冉, 代黎, 蔡瞻, 张大志, 姜远英. 协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究[J]. 药学实践与服务, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
ZHAO Jing, LI Ran, DAI Li, CAI Zhan, ZHANG Dazhi, JIANG Yuanying. Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
Citation: ZHAO Jing, LI Ran, DAI Li, CAI Zhan, ZHANG Dazhi, JIANG Yuanying. Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009

协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究

doi: 10.3969/j.issn.1006-0111.2016.02.009
基金项目: 国家自然科学基金(21272270)

Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans

  • 摘要: 目的 基于前期研究的胡椒乙胺和咖啡酸类化合物分别具有协同氟康唑(FCZ)抗耐药真菌的作用,将两类化合物结构片段通过适当的连接子连接,设计合成新型化合物,研究其体外抗耐药真菌活性。 方法 以胡椒乙胺为起始原料,与叔丁氧羰基保护的氨基酸缩合,随后脱保护基,再与咖啡酸缩合,形成目标化合物。对4个中间体和9个目标化合物进行体外协同FCZ抗耐药白念珠菌作用评价。 结果 9个目标化合物均具有协同FCZ(8.0μg/ml)抗耐药白念珠菌活性,MIC80为0.5~2.0μg/ml;其中, 3b、3f、3g、3i等化合物的MIC80均为0.5μg/ml,与对照化合物7b和5相当。 结论 将胡椒乙胺和咖啡酸通过4-哌啶甲酸(3b)、缬氨酸(3g)、亮氨酸(3f)、异亮氨酸(3i)连接,可以获得协同FCZ抗耐药真菌的高活性化合物。
  • [1] Lai CC, Tan CK, Huang YT, et al. Current challenges in the management of invasive fungal infections[J]. J Infect Chemother, 2008, 14(2):77-85.
    [2] Czaika V, Nenoff P, Glöckner A, et al. Detection of azole susceptibility patterns in clinical yeast strains isolated from 1998 to 2008[J]. New Microbiol, 2014, 37(4):465-494.
    [3] Liu SY, Hou YL, Chen X, et al. Combination of fluconazole with non-antifungal agents:a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery[J].Int J Antimicrob Agents, 2014, 43(5):395-402.
    [4] 谭善伦, 张大志, 姜远英. 具有协同抗耐药真菌活性的天然小分子化合物研究进展[J].药学学报, 2014, 49(8):1097-1104.
    [5] Quan H, Cao YY, Xu Z, et al. Potent in vitro synergism of fluconazole and berberine chloride against clinical isolates of Candida albicans resistant to fluconazole[J]. Antimicrob Agents Chemother, 2006, 50(3):1096-1099.
    [6] Cao YY, Dai BD, Wang Y, et al. In vitro activity of baicalein against Candida albicans biofilms[J]. Int J Antimicrob Agents, 2008, 32(1):73-77.
    [7] Huang S, Cao YY, Dai BD, et al. In vitro synergism of fluconazole and baicalein against clinical isolates of Candida albicans resistant to fluconazole[J]. Biol Pharm Bull, 2008, 31(12):2234-2236.
    [8] Liu W, Li LP, Zhang JD, et al. Synergistic antifungal effect of glabridin and fluconazole[J].PLoS One, 2014, 9:e103442.
    [9] Liu H, Wang L, Li Y, et al. Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans[J]. ChemMedChem, 2014, 9(1):207-216.
    [10] Dai L, Zang CX, Tian SJ, et al. Design,synthesis,and evaluation of caffeic acid amides as synergists to sensitize fluconazole-resistant Candida albicans to fluconazole[J]. Bioorg Med Chem Lett, 2015, 25(1):34-37.
    [11] Zhao X, Jia MX, Jiang XK,et al. Zipper-featured δ-peptide foldamers driven by donor-acceptor interaction. Design, synthesis, and characterization[J]. J Org Chem, 2004, 69(2):270-279.
    [12] Fu J, Cheng K, Zhang ZM, et al. Synthesis, structure and structure-activity relationship analysis of caffeic acid amides as potential antimicrobials[J]. Eur J Med Chem, 2010, 45(6):2638-2643.
    [13] Cappelletty DM, Rybak MJ. Comparison of methodologies for synergism testing of drug combinations against resistant strains of Pseudomonas aeruginosa[J].Antimicrob Agents Chemother, 1996, 40(3):677-683.
    [14] Segatore B, Bellio P, Setacci D, et al. In vitro interaction of usnic acid in combination with antimicrobial agents against methicillin-resistant Staphylococcus aureus clinical isolates determined by FICI and △E model methods[J]. Phytomedicine, 2012, 19(3-4):341-347.
    [15] Hung CC, Tsai WJ, Kuo LMY, et al. Evaluation of caffeic acid amide analogues as anti-platelet aggregation and anti-oxidative agents[J]. Bioorg Med Chem, 2005, 13(5):1791-1797.
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  • 收稿日期:  2016-01-04
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协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究

doi: 10.3969/j.issn.1006-0111.2016.02.009
    基金项目:  国家自然科学基金(21272270)

摘要: 目的 基于前期研究的胡椒乙胺和咖啡酸类化合物分别具有协同氟康唑(FCZ)抗耐药真菌的作用,将两类化合物结构片段通过适当的连接子连接,设计合成新型化合物,研究其体外抗耐药真菌活性。 方法 以胡椒乙胺为起始原料,与叔丁氧羰基保护的氨基酸缩合,随后脱保护基,再与咖啡酸缩合,形成目标化合物。对4个中间体和9个目标化合物进行体外协同FCZ抗耐药白念珠菌作用评价。 结果 9个目标化合物均具有协同FCZ(8.0μg/ml)抗耐药白念珠菌活性,MIC80为0.5~2.0μg/ml;其中, 3b、3f、3g、3i等化合物的MIC80均为0.5μg/ml,与对照化合物7b和5相当。 结论 将胡椒乙胺和咖啡酸通过4-哌啶甲酸(3b)、缬氨酸(3g)、亮氨酸(3f)、异亮氨酸(3i)连接,可以获得协同FCZ抗耐药真菌的高活性化合物。

English Abstract

赵晶, 李冉, 代黎, 蔡瞻, 张大志, 姜远英. 协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究[J]. 药学实践与服务, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
引用本文: 赵晶, 李冉, 代黎, 蔡瞻, 张大志, 姜远英. 协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究[J]. 药学实践与服务, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
ZHAO Jing, LI Ran, DAI Li, CAI Zhan, ZHANG Dazhi, JIANG Yuanying. Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
Citation: ZHAO Jing, LI Ran, DAI Li, CAI Zhan, ZHANG Dazhi, JIANG Yuanying. Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 129-134. doi: 10.3969/j.issn.1006-0111.2016.02.009
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