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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

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文章导航 > 药学实践与服务  > 2016 >  34(2): 129-134
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
shu
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
shu

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
  • 1.

    福建中医药大学药学院, 福建 福州 350122;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

  • 3.

    第二军医大学药学院, 新药研究中心, 上海 200433

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

  • 1.

    School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350112, China;Department of Organic Chemistry, Second Military Medical University, Shanghai 200433, China

  • 2.

    Department of Organic Chemistry, Second Military Medical University, Shanghai 200433, China

  • 3.

    New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

  • 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。
    Abstract: Objective 3,4-Methylenedioxyphenethylamine and caffeic acid derivatives have been proven previously in our group to produce activity against drug resistant fungi synergistic with fluconazole(FCZ). The two pharmacophores were coupled by amino acids as linkers in this project in order to design and synthesize the novel compounds and investigate the activity against drug resistant fungi in vitro. Methods 3,4-Methylenedioxyphenethylamine initially reacted with Boc-protected amino acids, following deprotection and coupling reaction with caffeic acid, to get nine title compounds. All title compounds as well as four intermediates were subjected to antifungal activity screening for fluconazole resistant Candida albicans in vitro. Results Nine title compounds showed synergistic antifungal activity for drug resistant Candida albicans with fluconazole at a concentration range of 0.5-2.0μg/ml. Among them, compounds 3b, 3f, 3g and 3i showed the higher activity with the same MIC80 value of 0.5μg/ml, which is comparable to those of the control compounds 7b and 5. Conclusion Linking 3,4-methylenedioxyphenethylamine and caffeic acid with piperidine-4-carboxylic acid(3b), valine(3g), leucine(3f) and isoleucine(3i) led to novel compounds with high synergistic antifungal activity against drug resistant Candida albicans combined with fluconazole.
  • [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
  • 修回日期:  2016-01-25

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
  • 1. 福建中医药大学药学院, 福建 福州 350122;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
  • 3. 第二军医大学药学院, 新药研究中心, 上海 200433
    • 基金项目:  国家自然科学基金(21272270)
  • 收稿日期: 2016-01-04
  • 修回日期: 2016-01-25

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
shu
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
shu

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