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Volume 34 Issue 2
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Article Navigation >  Journal of Pharmaceutical Practice and Service  > 2016  >  34(2): 129-134

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

doi: 10.3969/j.issn.1006-0111.2016.02.009
  • 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

  • Received Date: 2016-01-04
  • Rev Recd Date: 2016-01-25
  • 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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Design, synthesis and evaluation of the compounds combined with fluconazole against drug resistant Candida albicans

doi: 10.3969/j.issn.1006-0111.2016.02.009
  • 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
  • Received Date: 2016-01-04
  • Rev Recd Date: 2016-01-25

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.

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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