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

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

赵晶¹,
李冉²,
代黎²,
蔡瞻²,
张大志^1,,
姜远英^3,

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。
- 抗真菌 /
- 耐药 /
- 协同 /
- 合成 /
- 白念珠菌
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.
- antifungal /
- drug resistant /
- synergism /
- synthesis /
- Candida albicans

[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.

[1]	迟文雅, 袁艳, 李伟林, 吴茼妤, 俞媛. 负载骨髓间充质干细胞/白藜芦醇脂质体的水凝胶支架治疗创伤性脑损伤的研究 . 药学实践与服务, 2025, 43(2): 67-74. doi: 10.12206/j.issn.2097-2024.202406034
[2]	王文涛, 高兴, 赵凤平, 郑灿辉, 陈新. 异硒唑酮类化合物在疾病治疗中的作用和化学合成方法研究 . 药学实践与服务, 2025, 43(): 1-7. doi: 10.12206/j.issn.2097-2024.202308064
[3]	魏莱, 董国强, 盛春泉. 靶向SARS-CoV-2主蛋白酶的PROTAC设计、合成与蛋白降解活性研究 . 药学实践与服务, 2025, 43(5): 235-241, 258. doi: 10.12206/j.issn.2097-2024.202503063
[4]	李惠萍, 陈璐, 张琪金, 黄宝康. 紫苏叶挥发油成分的生物合成、含量测定及生物活性研究进展 . 药学实践与服务, 2025, 43(): 1-6. doi: 10.12206/j.issn.2097-2024.202412058
[5]	葛鹏程, 苏日古嘎, 任天舒, 党大胜. 硫酸黏菌素联合头孢哌酮舒巴坦治疗泛耐药鲍曼不动杆菌肺内感染的疗效分析 . 药学实践与服务, 2025, 43(): 1-4. doi: 10.12206/j.issn.2097-2024.202404093
[6]	郭灵怡, 刘艳超, 高路, 刘瑞瑶, 吕权真, 俞媛. 醋酸卡泊芬净单硬脂酸甘油酯纳米粒抗白色念珠菌感染的增效作用研究 . 药学实践与服务, 2025, 43(3): 136-142, 150. doi: 10.12206/j.issn.2097-2024.202310043
[7]	冯广伟, 张静, 刘阳熙, 崔敏. 消化道穿孔患者术后继发念珠菌血流感染的病例分析 . 药学实践与服务, 2025, 43(): 1-4. doi: 10.12206/j.issn.2097-2024.202312012
[8]	吴若南, 叶爽, 李墨晨轩, 缪震元, 罗川. 冬凌草甲素磺酰脲衍生物的设计与抗炎活性研究 . 药学实践与服务, 2025, 43(7): 335-338, 352. doi: 10.12206/j.issn.2097-2024.202401048
[9]	卢熠菲, 宋佳, 沈红霞, 赵庆杰. 新型苦参碱衍生物的设计合成与体外抗炎活性研究 . 药学实践与服务, 2025, 43(): 1-8. doi: 10.12206/j.issn.2097-2024.202503005
[10]	吴若南, 汤文敏, 高林, 吴岳林, 罗川, 缪震元. RRx-001衍生物的合成和抗肿瘤活性研究 . 药学实践与服务, 2025, 43(): 1-5. doi: 10.12206/j.issn.2097-2024.202408053
[11]	宋泽成, 马闪闪, 胡巧灵, 仲华, 王彦. 小檗碱与氟康唑合用抗氟康唑耐受白念珠菌的研究 . 药学实践与服务, 2025, 43(2): 87-91. doi: 10.12206/j.issn.2097-2024.202409047
[12]	施乔, 韩贵焱, 张俊腾, 刘娜. 新型Hsp90抑制剂的设计合成及其抗真菌和抗肿瘤活性研究 . 药学实践与服务, 2025, 43(3): 124-135. doi: 10.12206/j.issn.2097-2024.202501019
[13]	戴菲菲, 傅翔, 陈琼年, 俞苏纯. 上海某二级医院革兰阴性菌流行特征的回顾性分析 . 药学实践与服务, 2024, 42(12): 528-532. doi: 10.12206/j.issn.2097-2024.202305005
[14]	徐飞, 陈瑾, 鲁育含, 李志勇. 肠道菌群参与糖尿病肾病的机制研究进展 . 药学实践与服务, 2024, 42(5): 181-184, 197. doi: 10.12206/j.issn.2097-2024.202312023
[15]	尹小娟, 台力丽, 肖俊峰, 季波. 铜绿假单胞菌合并按蚊伊丽莎白菌肺部感染的病例分析 . 药学实践与服务, 2024, 42(5): 223-226. doi: 10.12206/j.issn.2097-2024.202310042
[16]	陈炳辰, 王思真, 郭贝贝, 杨峰. 紫杉醇棕榈酸酯的合成及其脂质体的制备与处方研究 . 药学实践与服务, 2024, 42(9): 379-384, 410. doi: 10.12206/j.issn.2097-2024.202404062
[17]	钱淑雨, 李铁军. 耐碳青霉烯类肠杆菌耐药机制的研究进展 . 药学实践与服务, 2024, 42(10): 419-425. doi: 10.12206/j.issn.2097-2024.202405005
[18]	杨媛媛, 安晓强, 许佳捷, 江键, 梁媛媛. 正极性驻极体联合5-氟尿嘧啶对瘢痕成纤维细胞生长抑制的协同作用 . 药学实践与服务, 2024, 42(6): 244-247. doi: 10.12206/j.issn.2097-2024.202310027
[19]	黄韵, 张正银, 金英, 郑怡菁, 李铁军, 孙莉莉. 耐碳青霉烯类肺炎克雷伯菌及大肠埃希菌临床分离株耐药性及耐药基因分析 . 药学实践与服务, 2024, 42(10): 439-444. doi: 10.12206/j.issn.2097-2024.202309059
[20]	史生辉, 石飞, 雷琼, 王亚峰, 吴雪花. 青藏高原肺结核合并念珠菌感染患者的病原菌分布特点及耐药率分析 . 药学实践与服务, 2024, 42(6): 260-262, 272. doi: 10.12206/j.issn.2097-2024.202304014

点击查看大图

计量

文章访问数: 4893
HTML全文浏览量: 535
PDF下载量: 41
被引次数: 0

姓名
邮箱
手机号码
标题
留言内容
验证码

留言板

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

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

计量

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

English Abstract

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

全文HTML

目录

留言板

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

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

计量

出版历程

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

English Abstract

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

全文HTML

目录

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