细菌外排泵抑制剂的合成及初步活性研究
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摘要
细菌耐药性问题日益突出并严重威胁人类健康。研究表明外排泵是细菌耐药的重要机制。外排泵位于耐药菌株内膜上,可将药物自细胞内排至周质及胞外,降低抗菌药物在细菌细胞内的有效浓度。有些化合物本身无明显抗菌活性但可抑制细菌外排作用,这类化合物称为外排泵抑制剂。外排泵抑制剂与抗菌药物联用能有效对抗耐药菌。因此对其研究与开发有望成为恢复药物敏感性,解决耐药性问题的重要途径。本文合成一系列外排泵抑制剂类似物并对其抗菌活性做了初步研究,另外还对具有抗菌活性的水杨酰苯胺衍生物的合成做了一些探索。
第二章以槲皮素和异丁香酚为原料合成了黄酮木质素类化合物I,并通过质谱,核磁氢谱进行了表征,该化合物未见文献报道；合成了9个吡啶二羧酸酯类化合物,并通过溶剂和催化剂的选择对反应条件进行了优化；以芳香酮和4-硝基苯肼为原料合成2-芳基-5-硝基吲哚。第三章以水杨酸和对氨基酚为原料对水杨酰苯胺类化合物的合成做了一些探索。
第四章以固体平板抑菌圈和液体最低抑菌浓度测定法对部分化合物的抗菌活性进行了研究。结果表明这些化合物与环丙沙星联用可降低环丙沙星的最低抑菌浓度,有效抑制金黄色葡萄球菌耐药菌株。另外化合物I与左氧氟沙星、小檗碱联用时也表现出良好的抗耐药活性。
Bacterial resistance is an increasingly serious problem which threatening the human and animals. Research shows that efflux pump of bacterial is an important mechanism of the resistance. Efflux pump which exists on the intracellular membrane of drug-resistant strains can decrease the effective concentration inside of bacterial by pump out drug from cells. Inhibitor of efflux pump has no effective antibacterial activity itself. But it could reverse the drug resistance by inhibiting the efflux pump. So the research and development of efflux pump inhibitor may become an important way to solve the problem of bacterial resistance. In this dissertation, the analogues of known efflux pump inhibitors were designed and synthesized and their antimicrobial activity were evaluated. The salicylanilide analogues which possess antibacterial activity were also synthesized.
In the Chapter Two, a new flavone was synthesized from quercetin and isoeugenol and characterized by MS and 1HNMR. Nine 2,6-dimethyl-4-arylpyridine-3,5-dicarboxylic acid diethyl esters were synthesized and characterized. The reaction conditions were optimizing by choosing suitable solvent and catalyst. The synthesis of 2-aryl-5-nitro-lH-indoles was explored use aromatic ketones and 4-Nitrophenylhydrazine as starting material. The synthesis of salicylanilide analogues was explored in the Chapter Three.
In the Chapter Four, the antimicrobial activity of some synthetic compounds combined with antibacterial drugs was evaluated. Inhibition zone and minimal inhibitory concentration were used as evaluation criterion. The mixture of Ciprofloxacin and any one of these compounds can lower the minimal inhibitory concentration of Ciprofloxacin in drug resistant strains, therefore they can inhibit the drug resistant strains of Staphylococcus aureus effectively.
第二章以槲皮素和异丁香酚为原料合成了黄酮木质素类化合物I,并通过质谱,核磁氢谱进行了表征,该化合物未见文献报道；合成了9个吡啶二羧酸酯类化合物,并通过溶剂和催化剂的选择对反应条件进行了优化；以芳香酮和4-硝基苯肼为原料合成2-芳基-5-硝基吲哚。第三章以水杨酸和对氨基酚为原料对水杨酰苯胺类化合物的合成做了一些探索。
第四章以固体平板抑菌圈和液体最低抑菌浓度测定法对部分化合物的抗菌活性进行了研究。结果表明这些化合物与环丙沙星联用可降低环丙沙星的最低抑菌浓度,有效抑制金黄色葡萄球菌耐药菌株。另外化合物I与左氧氟沙星、小檗碱联用时也表现出良好的抗耐药活性。
Bacterial resistance is an increasingly serious problem which threatening the human and animals. Research shows that efflux pump of bacterial is an important mechanism of the resistance. Efflux pump which exists on the intracellular membrane of drug-resistant strains can decrease the effective concentration inside of bacterial by pump out drug from cells. Inhibitor of efflux pump has no effective antibacterial activity itself. But it could reverse the drug resistance by inhibiting the efflux pump. So the research and development of efflux pump inhibitor may become an important way to solve the problem of bacterial resistance. In this dissertation, the analogues of known efflux pump inhibitors were designed and synthesized and their antimicrobial activity were evaluated. The salicylanilide analogues which possess antibacterial activity were also synthesized.
In the Chapter Two, a new flavone was synthesized from quercetin and isoeugenol and characterized by MS and 1HNMR. Nine 2,6-dimethyl-4-arylpyridine-3,5-dicarboxylic acid diethyl esters were synthesized and characterized. The reaction conditions were optimizing by choosing suitable solvent and catalyst. The synthesis of 2-aryl-5-nitro-lH-indoles was explored use aromatic ketones and 4-Nitrophenylhydrazine as starting material. The synthesis of salicylanilide analogues was explored in the Chapter Three.
In the Chapter Four, the antimicrobial activity of some synthetic compounds combined with antibacterial drugs was evaluated. Inhibition zone and minimal inhibitory concentration were used as evaluation criterion. The mixture of Ciprofloxacin and any one of these compounds can lower the minimal inhibitory concentration of Ciprofloxacin in drug resistant strains, therefore they can inhibit the drug resistant strains of Staphylococcus aureus effectively.
引文
[1]徐海花,牛钟相,秦爱建,张万福.细菌耐药性研究进展[J].山东农业大学学报(自然科学版),2010,41(1)：156-160
[2]顾欣,金凌艳,蔡金华,等.国家动物源细菌耐药性监测工作的探讨和建议[J].中国兽药杂志,2009,43(7)：45-50,53
[3]任祥友,蒋瑞芹,崔玉芹.抗生素的细菌耐药性及应对措施[J].中国民康医学,2010,22(13)：1736-1737
[4]王瑞兰.细菌耐药性产生的原因及对细菌耐药性应采取的对策[J].现代中西医结合杂志,2006,15(15)：2077-2078
[5]Van B. F., Tulkens P. M. Macroides:pharmacokincs and pharmacodynamics [J]. Int J An-timicrob Agents,2001,18 (Suppl 1):17
[6]Lomovskaya O., Watkins W J. Efflux pumps:their role in antibacterial drug discovery[J]. Curr Med Chem,2001,8(14):1699
[7]Yoshida H., Bogaki M., Nakamura S., et al. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones[J]. J Bacteriol, 1990,172(12):6942
[8]刘忆霜,肖春玲.细菌多重耐药外排泵抑制剂研究进展[J].中国抗生素杂志,2007,32(4)：211-216,244
[9]孙瑞元.药理学[M].北京：人民军医出版社,2001：268
[10]李世学.含茚酮骨架化合物的合成与抑菌活性研究[D].西安：西北大学,2009
[11]咸瑞卿,马淑涛NorA多药耐药外排泵抑制剂研究进展[J].中国药学杂志,2007,42(14)：1045-1048,1120
[12]Markham P. N., Neyfakh A. A. Efflux-mediated drug resistance in Gram-positive bacter-ia[J]. Curr Opin Microbiol,2001,4(5):509-514
[13]Lewis K. In search of natural substrates and inhibitors of MDR pumps[J]. J Mol Microbi-ol Biotechnol,2001,3(2):247-254
[14]Yu J L, Grinius L., Hooper D. C. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes[J]. J Bacteriol,2002,184 (5):1370-1377
[15]Markham P. N. Inhibition of the emergenee of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine[J]. Antimicrob Agents Chemother, 1999,43(4):988-989
[16]Ferte J., Kuhnel J. M., Chapuis G., et al. Flavonoid-related modulators of multidrug resi-stance:synthesis, pharmacological activity, and structure-activity relationships[J]. J Med Chem,1999,42(3):478-489
[17]Guz N. R., Stermitz F. R., Johnson J. B., et al. Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump structure-activity relationships[J]. J Med Chem,2001,44(2):261-268
[18]Morel C., Stermitz F. R., Tegos G., et al. Isoflavones as potentiators of antibacterial acti-vity[J]. J Agric Food Chem,2003,51(19):5677-5679
[19]Belofsky G., Percivill D., Lewis K., et al. Phenolic metabolites of Dalea versicolor that enhance antibiotic activity against model pathogenic bacteria[J]. J Nat Prod,2004,67(3): 481-484
[20]Stermitz F. R., Lorenz P., Tawara J. N., et al. Synergy in a medicinal plant:antimicrobial action of berberine potentiated by 5-methoxyhydnocarpin,a multidrug pump inhibitor[J].Proc Natl Acad Sci,2000,97(4):1433-1437
[21]Neyfakh A. A., Bidnenko V. E., Chen L. B. Efflux-mediated multidrug resisitance in Ba-cillus subtilis:similarities and dissimilarities with the mammalian system[J]. Proc Natl Acad Sci,1991,88(6):4781-4785
[22]Chung H. P., Siegel S. A., Rogers B., et al. Bacteria lacking a multidrug pump:a sensiti-ve tool for drug discovery[J]. Proc Natl Acad Sci,1998,95(6):6602-6606
[23]杨再昌,杨小生,郝小江,等.细菌外排泵抑制剂[J].中国药科大学学报,2005,36(4)：381-384
[24]Markham P. N., Westhaus E., Klyachko K., et al. Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus[J]. Antimicrob Agents Chem- other,1999, 43(10):2404-2408
[25]Kaatz G. W., Moudgal V. V., Seo S. M., et al. Phenylpiperidine selective serotonin reuptake inhibitors interfere with muhidrug efflux pump activity in Staphylococcus aureus[J]. Int J Antimicrob Agent,2003,22(3):254-261
[26]Gibbons S., Oluwatuyl M., Kaatz G. W. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus[J]. J Antimicrob Chemother,2003,51(1):13-17
[27]Kaatz G. W., Moudgal V. V., Seo S. M., et al. Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in staphylococcus aureus[J]. Antimicrobial Agent and Chemotherapy,2003,47(2):719-726
[28]Marquez B., Neuville L., Moreau N. J., et al. Muhidrug resistance reversal agent from Jatropha elliptica[J]. Phytoohemistry,2005,66(15):1804-1811
[29]Asoh K., Saburi Y., Sato S., et al. Potentiation of some anticancer agents by dipyridamol-e against drug-sensitive and drug-resistant cancer cell lines[J]. Jpn. J. Cancer. Res.,1989,80, 475-481
[30]Kawase M., Shah A., Gaveriya H., et al.3,5-Dibenzoyl-1,4-dihydropyridines:synthesis and MDR reversal in tumor cells[J]. Bioorg. Med. Chem.,2002,10,1051-1055
[31]Avendano C., Menendez J.C. Inhibitors of multidrug resistance to antitumor agents (MDR)[J]. Curr. Med. Chem.,2002,9,159-193
[32]Pereda-Miranda R., Kaatz G. W., Gibbons S. Polyacylated oligosaccharides from medicinal mexican morning glory species as antibacterials and inhihitors of multidrug resistance in staphylococcus aureus[J]. J Nat Prod,2006,69(3):406-409
[33]Stermitz F. R., Tawara-Matsuda J., Lorenz P., et al.5'-methoxyhydnocarpin-D and pheophorbide A:Berberis species components that potentiate berberine growth inhibition of resistant Staphylococcus aureus [J]. J Nat Prod,2000,63(8):1146
[34]Oluwatuyi M., Kaatz G. W., Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis[J]. Phytochemistry,2004,65(24):3249
[35]Maria R. F., JOSIANE S. L., ALDENIR F. S., et al. Anti-bacterial activity of some Brazilian medicinal plants[J]. J Ethrvopharmacol,2006,105(1-2):137-147
[36]Lomovskaya O., Warren M., Lee A., et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa:novel agents for combination therapy[J]. Antimicrob Agents Chemother,2001,45(1):105-116
[37]Nelson M. L., Levy S. B., Reversal of tetracycline resistance mediated by different bacterialtetracycline resistance determinants by an inhibitor of the Tet (B) antiport protein[J]. Antimicrob Agents Chemother,1999,43(7):1719-1724
[38]Hirata T., Wakatabe R., Nielsen J., et al. Screening of an inhibitor of the tetracycline efflux pump in a tetracycline-resistant clinical-isolate of Staphylococcus aureus 743[J]. Bio Pharm Bull,1998,21(7):678-681
[39]王旭,黄永茂.大肠埃希菌外排泵AcrAB-TolC研究相关进展[J].重庆医学,2010,39(19)：2670-2673
[40]Touze T., Eswaran J., Bokma E., et al. Interactions underlying assembly of the escherich-ia coli AcrAB-TolC multidrug efflux system[J]. J Mol Microbiol,2004,53(2):697
[41]Monique M., Abdallah M., Jacqueline C., et al. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates[J]. Biochem J,2003, 376:801-805
[42]Samosorn S., Bremner J. B., Baijl A., et al. Synthesis of functionalized 2-aryl-5-nitro-1H-indoles and their activity as bacterial NorA effiux pump inhibitors [J]. Bioorg Med Chem,2006,14(3):857-865
[43]Lee Y., Yeo H., Liu S-H. Increased Anti-P-glycoprotein Activity of Baicalein by Alkylation on the A Ring[J]. J. Med. Chem.2004,47:5555-5566
[44]Ball A. R., Casadei G, Samosorn S., et al. Conjugating Berberine to a Multidrug Resistance Pump Inhibitor Creates an Effective Antimicrobial[J]. Chemical Biology.2006, 1(9):594-600
[45]Guz N. R., Stemritz F. R., Jobnson J. B., et al. Flavonolignan and flavone inhibittors of a Staphylococcus aureus multidrug resistance pump:structure-activity relationships[J]. Journal of Medicinal Chemistry,2001,44(2):261-8
[46]Vanden E. J.-J., Delfosse F., Mayence A., et al. Old reagents, new results:Aromatization of Hantzsch 1,4-dihydropyridines with manganese dioxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone[J]. Tetrahedron,1995,51:6511-6516
[47]Navarrete-Encina P. A., Squella J. A., Carbajo J., et al. Synthesis of some C-3,4,5-substi-tuted 2,6-dimethyl-1,4-dihydropyridines (4-DHPs)[J]. Synthetic Communications,2007,37 (12):2051-2060
[48]Petrow V., Rewald E. L.4-Aryl-2,6-dimethyl-3-pyridinecarboxylic acids[P]. GB 619241 19490307
[49]Arumugam P., Perumal P. T. Hantzsch synthesis of polyhydroquinolines. A simple, efficient and neat protocol[J]. Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry,2008,47B(7):1084-1090
[50]Zeynizadeh B., Dilmaghani K. A., Mirzaei M. Mild and convenient method for aromatization of Hantzsch esters of 1,4-dihydropyridines with Ag2O[J]. Acta Chimica Slovenica,2007,54(2):366-369
[51]Zeynizadeh B., Dilmaghani K. A., Mirzaei M. Mild and efficient method for aromatization of Hantzsch esters of 1,4-dihydropyridines with HIO3[J]. Asian Journal of Chemistry,2009,21(4):2969-2972
[52]Shaabani A., Rezayan A. H., Rahmati A., et al. Ultrasound-accelerated synthesis of 1,4-dihydropyridines in an ionic liquid[J]. Monatshefte fuer Chemie,2006,137(1):77-81
[53]Shinde S. V., Jadhav W. N. Oxidative aromatization of Hantzsch 1,4-dihydropyridines using NaBrO3/NaHSO3[J]. India. Organic Chemistry:An Indian Journal,2009,5(1):19-22
[54]Abrego V. H., Martinez-Perez B., Torres L. A., et al. Antihypertensive and antiarrhythmi-c properties of a para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP compound: Comparison with other compounds of the same kind and relationship with logP values[J]. European Journal of Medicinal Chemistry,2010,45(10):4622-4630
[55]Montazerozohori M., Karami B., Nasr-Esfahani M. et al. Silver salts/iodine monochlori-de as a new oxidation system for the oxidative aromatization of 1,4-dihydropy-ridines[J]. Heterocyclic Communications,2007,13(5):289-294
[56]Debache A., Ghalem W., Boulcina R. An efficient one-step synthesis of 1,4-dih-ydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions[J]. Tetrahedron Letters,2009,50(37):5248-5250
[57]Yadav J. S., Reddy B. V. S., Basak A. K. Lodoxybenzoic acid (IBX):an efficient and novel oxidizing agent for the aromatization of 1,4-dihydropyridines[J]. Synthesis,2006,3: 451-454
[58]Jarikote D. V., Deshmukh R. R., Rajagopal R., et al. Ultrasound promoted facile synthesis of arylhydrazones at ambient conditions[J]. Ultrasonics Sonochemistry,2003,10(1): 45-48
[59]Dennler E. B., Frasca A. R. Synthesis of indazoles using polyphosphoric acid[J]. I. Tetrahedron,1966,22(9):3131-3141
[60]Lupea A. X., Padure M. Synthesis and characterization of some N-substituted amides of salicylic acid[J]. Zbornik Matice Srpske za Prirodne Nauke,2004,104:5-10
[61]Cheng T. R., Wu Y. T., Yang S. T., et al. High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus(MRSA) and the transglycosylase[J]. Bioorganic & Medicinal Chemistry,2010,18:8512-8529
[2]顾欣,金凌艳,蔡金华,等.国家动物源细菌耐药性监测工作的探讨和建议[J].中国兽药杂志,2009,43(7)：45-50,53
[3]任祥友,蒋瑞芹,崔玉芹.抗生素的细菌耐药性及应对措施[J].中国民康医学,2010,22(13)：1736-1737
[4]王瑞兰.细菌耐药性产生的原因及对细菌耐药性应采取的对策[J].现代中西医结合杂志,2006,15(15)：2077-2078
[5]Van B. F., Tulkens P. M. Macroides:pharmacokincs and pharmacodynamics [J]. Int J An-timicrob Agents,2001,18 (Suppl 1):17
[6]Lomovskaya O., Watkins W J. Efflux pumps:their role in antibacterial drug discovery[J]. Curr Med Chem,2001,8(14):1699
[7]Yoshida H., Bogaki M., Nakamura S., et al. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones[J]. J Bacteriol, 1990,172(12):6942
[8]刘忆霜,肖春玲.细菌多重耐药外排泵抑制剂研究进展[J].中国抗生素杂志,2007,32(4)：211-216,244
[9]孙瑞元.药理学[M].北京：人民军医出版社,2001：268
[10]李世学.含茚酮骨架化合物的合成与抑菌活性研究[D].西安：西北大学,2009
[11]咸瑞卿,马淑涛NorA多药耐药外排泵抑制剂研究进展[J].中国药学杂志,2007,42(14)：1045-1048,1120
[12]Markham P. N., Neyfakh A. A. Efflux-mediated drug resistance in Gram-positive bacter-ia[J]. Curr Opin Microbiol,2001,4(5):509-514
[13]Lewis K. In search of natural substrates and inhibitors of MDR pumps[J]. J Mol Microbi-ol Biotechnol,2001,3(2):247-254
[14]Yu J L, Grinius L., Hooper D. C. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes[J]. J Bacteriol,2002,184 (5):1370-1377
[15]Markham P. N. Inhibition of the emergenee of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine[J]. Antimicrob Agents Chemother, 1999,43(4):988-989
[16]Ferte J., Kuhnel J. M., Chapuis G., et al. Flavonoid-related modulators of multidrug resi-stance:synthesis, pharmacological activity, and structure-activity relationships[J]. J Med Chem,1999,42(3):478-489
[17]Guz N. R., Stermitz F. R., Johnson J. B., et al. Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump structure-activity relationships[J]. J Med Chem,2001,44(2):261-268
[18]Morel C., Stermitz F. R., Tegos G., et al. Isoflavones as potentiators of antibacterial acti-vity[J]. J Agric Food Chem,2003,51(19):5677-5679
[19]Belofsky G., Percivill D., Lewis K., et al. Phenolic metabolites of Dalea versicolor that enhance antibiotic activity against model pathogenic bacteria[J]. J Nat Prod,2004,67(3): 481-484
[20]Stermitz F. R., Lorenz P., Tawara J. N., et al. Synergy in a medicinal plant:antimicrobial action of berberine potentiated by 5-methoxyhydnocarpin,a multidrug pump inhibitor[J].Proc Natl Acad Sci,2000,97(4):1433-1437
[21]Neyfakh A. A., Bidnenko V. E., Chen L. B. Efflux-mediated multidrug resisitance in Ba-cillus subtilis:similarities and dissimilarities with the mammalian system[J]. Proc Natl Acad Sci,1991,88(6):4781-4785
[22]Chung H. P., Siegel S. A., Rogers B., et al. Bacteria lacking a multidrug pump:a sensiti-ve tool for drug discovery[J]. Proc Natl Acad Sci,1998,95(6):6602-6606
[23]杨再昌,杨小生,郝小江,等.细菌外排泵抑制剂[J].中国药科大学学报,2005,36(4)：381-384
[24]Markham P. N., Westhaus E., Klyachko K., et al. Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus[J]. Antimicrob Agents Chem- other,1999, 43(10):2404-2408
[25]Kaatz G. W., Moudgal V. V., Seo S. M., et al. Phenylpiperidine selective serotonin reuptake inhibitors interfere with muhidrug efflux pump activity in Staphylococcus aureus[J]. Int J Antimicrob Agent,2003,22(3):254-261
[26]Gibbons S., Oluwatuyl M., Kaatz G. W. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus[J]. J Antimicrob Chemother,2003,51(1):13-17
[27]Kaatz G. W., Moudgal V. V., Seo S. M., et al. Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in staphylococcus aureus[J]. Antimicrobial Agent and Chemotherapy,2003,47(2):719-726
[28]Marquez B., Neuville L., Moreau N. J., et al. Muhidrug resistance reversal agent from Jatropha elliptica[J]. Phytoohemistry,2005,66(15):1804-1811
[29]Asoh K., Saburi Y., Sato S., et al. Potentiation of some anticancer agents by dipyridamol-e against drug-sensitive and drug-resistant cancer cell lines[J]. Jpn. J. Cancer. Res.,1989,80, 475-481
[30]Kawase M., Shah A., Gaveriya H., et al.3,5-Dibenzoyl-1,4-dihydropyridines:synthesis and MDR reversal in tumor cells[J]. Bioorg. Med. Chem.,2002,10,1051-1055
[31]Avendano C., Menendez J.C. Inhibitors of multidrug resistance to antitumor agents (MDR)[J]. Curr. Med. Chem.,2002,9,159-193
[32]Pereda-Miranda R., Kaatz G. W., Gibbons S. Polyacylated oligosaccharides from medicinal mexican morning glory species as antibacterials and inhihitors of multidrug resistance in staphylococcus aureus[J]. J Nat Prod,2006,69(3):406-409
[33]Stermitz F. R., Tawara-Matsuda J., Lorenz P., et al.5'-methoxyhydnocarpin-D and pheophorbide A:Berberis species components that potentiate berberine growth inhibition of resistant Staphylococcus aureus [J]. J Nat Prod,2000,63(8):1146
[34]Oluwatuyi M., Kaatz G. W., Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis[J]. Phytochemistry,2004,65(24):3249
[35]Maria R. F., JOSIANE S. L., ALDENIR F. S., et al. Anti-bacterial activity of some Brazilian medicinal plants[J]. J Ethrvopharmacol,2006,105(1-2):137-147
[36]Lomovskaya O., Warren M., Lee A., et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa:novel agents for combination therapy[J]. Antimicrob Agents Chemother,2001,45(1):105-116
[37]Nelson M. L., Levy S. B., Reversal of tetracycline resistance mediated by different bacterialtetracycline resistance determinants by an inhibitor of the Tet (B) antiport protein[J]. Antimicrob Agents Chemother,1999,43(7):1719-1724
[38]Hirata T., Wakatabe R., Nielsen J., et al. Screening of an inhibitor of the tetracycline efflux pump in a tetracycline-resistant clinical-isolate of Staphylococcus aureus 743[J]. Bio Pharm Bull,1998,21(7):678-681
[39]王旭,黄永茂.大肠埃希菌外排泵AcrAB-TolC研究相关进展[J].重庆医学,2010,39(19)：2670-2673
[40]Touze T., Eswaran J., Bokma E., et al. Interactions underlying assembly of the escherich-ia coli AcrAB-TolC multidrug efflux system[J]. J Mol Microbiol,2004,53(2):697
[41]Monique M., Abdallah M., Jacqueline C., et al. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates[J]. Biochem J,2003, 376:801-805
[42]Samosorn S., Bremner J. B., Baijl A., et al. Synthesis of functionalized 2-aryl-5-nitro-1H-indoles and their activity as bacterial NorA effiux pump inhibitors [J]. Bioorg Med Chem,2006,14(3):857-865
[43]Lee Y., Yeo H., Liu S-H. Increased Anti-P-glycoprotein Activity of Baicalein by Alkylation on the A Ring[J]. J. Med. Chem.2004,47:5555-5566
[44]Ball A. R., Casadei G, Samosorn S., et al. Conjugating Berberine to a Multidrug Resistance Pump Inhibitor Creates an Effective Antimicrobial[J]. Chemical Biology.2006, 1(9):594-600
[45]Guz N. R., Stemritz F. R., Jobnson J. B., et al. Flavonolignan and flavone inhibittors of a Staphylococcus aureus multidrug resistance pump:structure-activity relationships[J]. Journal of Medicinal Chemistry,2001,44(2):261-8
[46]Vanden E. J.-J., Delfosse F., Mayence A., et al. Old reagents, new results:Aromatization of Hantzsch 1,4-dihydropyridines with manganese dioxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone[J]. Tetrahedron,1995,51:6511-6516
[47]Navarrete-Encina P. A., Squella J. A., Carbajo J., et al. Synthesis of some C-3,4,5-substi-tuted 2,6-dimethyl-1,4-dihydropyridines (4-DHPs)[J]. Synthetic Communications,2007,37 (12):2051-2060
[48]Petrow V., Rewald E. L.4-Aryl-2,6-dimethyl-3-pyridinecarboxylic acids[P]. GB 619241 19490307
[49]Arumugam P., Perumal P. T. Hantzsch synthesis of polyhydroquinolines. A simple, efficient and neat protocol[J]. Indian Journal of Chemistry, Section B:Organic Chemistry Including Medicinal Chemistry,2008,47B(7):1084-1090
[50]Zeynizadeh B., Dilmaghani K. A., Mirzaei M. Mild and convenient method for aromatization of Hantzsch esters of 1,4-dihydropyridines with Ag2O[J]. Acta Chimica Slovenica,2007,54(2):366-369
[51]Zeynizadeh B., Dilmaghani K. A., Mirzaei M. Mild and efficient method for aromatization of Hantzsch esters of 1,4-dihydropyridines with HIO3[J]. Asian Journal of Chemistry,2009,21(4):2969-2972
[52]Shaabani A., Rezayan A. H., Rahmati A., et al. Ultrasound-accelerated synthesis of 1,4-dihydropyridines in an ionic liquid[J]. Monatshefte fuer Chemie,2006,137(1):77-81
[53]Shinde S. V., Jadhav W. N. Oxidative aromatization of Hantzsch 1,4-dihydropyridines using NaBrO3/NaHSO3[J]. India. Organic Chemistry:An Indian Journal,2009,5(1):19-22
[54]Abrego V. H., Martinez-Perez B., Torres L. A., et al. Antihypertensive and antiarrhythmi-c properties of a para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP compound: Comparison with other compounds of the same kind and relationship with logP values[J]. European Journal of Medicinal Chemistry,2010,45(10):4622-4630
[55]Montazerozohori M., Karami B., Nasr-Esfahani M. et al. Silver salts/iodine monochlori-de as a new oxidation system for the oxidative aromatization of 1,4-dihydropy-ridines[J]. Heterocyclic Communications,2007,13(5):289-294
[56]Debache A., Ghalem W., Boulcina R. An efficient one-step synthesis of 1,4-dih-ydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions[J]. Tetrahedron Letters,2009,50(37):5248-5250
[57]Yadav J. S., Reddy B. V. S., Basak A. K. Lodoxybenzoic acid (IBX):an efficient and novel oxidizing agent for the aromatization of 1,4-dihydropyridines[J]. Synthesis,2006,3: 451-454
[58]Jarikote D. V., Deshmukh R. R., Rajagopal R., et al. Ultrasound promoted facile synthesis of arylhydrazones at ambient conditions[J]. Ultrasonics Sonochemistry,2003,10(1): 45-48
[59]Dennler E. B., Frasca A. R. Synthesis of indazoles using polyphosphoric acid[J]. I. Tetrahedron,1966,22(9):3131-3141
[60]Lupea A. X., Padure M. Synthesis and characterization of some N-substituted amides of salicylic acid[J]. Zbornik Matice Srpske za Prirodne Nauke,2004,104:5-10
[61]Cheng T. R., Wu Y. T., Yang S. T., et al. High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus(MRSA) and the transglycosylase[J]. Bioorganic & Medicinal Chemistry,2010,18:8512-8529