异噁唑衍生物的合成及其活性测试
|
摘要
当前,对抗耐药菌制剂的需求是一个全球性的问题。人们越来越关注具有多重耐药性的革兰氏阳性菌所导致的感染。具有多重耐药性的革兰氏阳性菌的菌种包括:耐甲氧苯青霉素金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus, MRSA)、耐甲氧苯青霉素表皮葡萄球菌(Methicillin-resistant Staphylococcus epidermidis , MRSE)、耐万古霉素粪肠球菌(Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, VREF)和耐青霉素与头孢菌素的肺炎链球菌。上述病原体直接影响医院和社区发病率和死亡率。噁唑烷酮类化合物是一类新型的具有良好发展前景的抗菌药,其代表药物是利奈唑酮(PNU-100766,商品名Zyvox)。近来,利奈唑酮在国外被用于治疗由革兰氏阳性菌所造成的感染。噁唑烷酮类化合物可以选择性的与50S核糖体亚基的23SRNA部分结合,阻止功能性的70S起始因子的形成,从而阻断蛋白质合成的初始阶段。鉴于其独特的作用机理,噁唑烷酮类抗菌剂很少与其它类抗菌剂产生交叉耐药性。
有关噁唑烷酮类化合物构效关系研究的文献报道,异噁唑环是噁唑烷酮环的生物电子等排体之一。同时,含有异噁唑环的化合物中有些被用来开发作为除菌剂。
根据拼合原理,本文合成了45个新化合物,并且对这些化合物药理活性进行了体外活性测试,其中有7个抑菌活性比较好的化合物。这几个化合物的体内抑菌活性还需要进行广泛测试,其药物代谢、药物毒理学方面的安全性问题还需要进一步的考察。
The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens. Principal players among these problematic organisms are isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), vancomycinresistant Enterococcus faecalis and Enterococcus faecium (VREF), and also penicillin and cephalosporin resistant Streptococcus pneumoniae. These pathogens are responsible for significant morbidity and mortality in both the hospital and community setting. A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram positive bacteria. The oxazolidinone class of antibacterial agents selectively binds to the 23S RNA component of the 50S ribosomal subunit and prevents the formation of a functional 70S initiation complex, inhibiting protein synthesis at the early stage. Due to its unique mechanism of action, there are fewer cross-resistances between the oxazolidinones and other families of antibacterial agents. Previous literature on the structure-activity relationships for the oxazolidinones has demonstrated that the oxazolidinone ring and the isoxazoline ring are bioisosteres. Furthermore, the compounds carrying isoxazoline ring can be used for the protection of plant from diseases, and fungicidal against phytophthora infestation on tomatoes. About 45 compounds were synthesized according to the combination principles.
The antibacterial activity of the new compounds has been tested. Fortunately, some of the compounds have novel antibacterial activity. Studies to establish their in vivo efficacy and safety are being planned for further development.
有关噁唑烷酮类化合物构效关系研究的文献报道,异噁唑环是噁唑烷酮环的生物电子等排体之一。同时,含有异噁唑环的化合物中有些被用来开发作为除菌剂。
根据拼合原理,本文合成了45个新化合物,并且对这些化合物药理活性进行了体外活性测试,其中有7个抑菌活性比较好的化合物。这几个化合物的体内抑菌活性还需要进行广泛测试,其药物代谢、药物毒理学方面的安全性问题还需要进一步的考察。
The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens. Principal players among these problematic organisms are isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), vancomycinresistant Enterococcus faecalis and Enterococcus faecium (VREF), and also penicillin and cephalosporin resistant Streptococcus pneumoniae. These pathogens are responsible for significant morbidity and mortality in both the hospital and community setting. A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram positive bacteria. The oxazolidinone class of antibacterial agents selectively binds to the 23S RNA component of the 50S ribosomal subunit and prevents the formation of a functional 70S initiation complex, inhibiting protein synthesis at the early stage. Due to its unique mechanism of action, there are fewer cross-resistances between the oxazolidinones and other families of antibacterial agents. Previous literature on the structure-activity relationships for the oxazolidinones has demonstrated that the oxazolidinone ring and the isoxazoline ring are bioisosteres. Furthermore, the compounds carrying isoxazoline ring can be used for the protection of plant from diseases, and fungicidal against phytophthora infestation on tomatoes. About 45 compounds were synthesized according to the combination principles.
The antibacterial activity of the new compounds has been tested. Fortunately, some of the compounds have novel antibacterial activity. Studies to establish their in vivo efficacy and safety are being planned for further development.
引文
[1] Michael R. Barbachyn, Gary J. Cleek, Lester A. Dolak, et al, Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens, J. Med. Chem. 2003, 46(2): 284-302.
[2]雷连成.中国兽药杂志,2002,36(11):41-44。
[3]张国强,钱卫东,张立昌等,克服细菌耐药性的新药及其临床应用,国外畜牧学—猪与禽,2003,23(1):60-61。
[4]尤启冬,药物化学,化学工业出版社,北京,2004。
[5] A.M. Slee, M. A. Wuonola, R. J. McRipley,etal. Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrob.Agents Chemother., 1987, 31, 1791.
[6] Gonzales RD, Schreckenberger PC, Graham MB, et a1. Infections due to vancomycin-resistance Enterococcus faecium resistance to linezolid [J]. Lancet, 2001, 357 (9263): 1179.
[7] Nilius AM. Have the oxazolidinones lived up to their billing? Future perspectives for this antibacterial class [J]. Current Opinion Invest Drugs, 2003, 4(2): 149-155.
[8] Daly JS, Eliopoulos GM, Reiszner, et a1. Activity and mechanism of action of DuP105 and DuP721, new oxazolidinone compounds [J]. J Antimicrob Chemother, 1988, 21(6): 721-730.
[9] Slee AM, Wuonola MA, Mcripley RJ, et al. Oxazolidinones, a new class of synthetic antibacterial agent: in vitro and in vivo activities of DuP105 and DuP721 [J]. Antimicrob Agents Chemother, 1987, 31(11): 1791-1797.
[10] Kaatz GW, Seo SM. In vitro activities of oxazolidinone compounds U-100592 and U-100766 against Staphylococcus aureus and Staphylococcus epidermidis [J]. Antimicrob Agents Chemother, 1996, 40(3): 799-801.
[11] Kloss, P., Xiong, L., Shinabarger, D. and Mankin, A.S. Resistance mutations in 23S rRNA identify the site of action of protein synthesis inhibitor, linezolid, in the ribosomal peptidyl transferase center. J. Mol. Biol., 1999, 294(2): 93-101.
[12]陈代杰。抗菌药物与细菌耐药性。华东理工大学出版社。2001年第一版。
[13] Clemett D, Markham A. Linezolid [J]. Drugs Fut, 2000, 59(4) : 815-827.
[14] Fines M, Leclercq R. Activity of linezolid against Gram-positive cocci possessing genes conferring resistance to protein synthesis inhibitors. Antimicrob Chemother, 2000, 45(4): 797.
[15] A H Lin, R W Murray, T J Vidmar, and K R Marotti. The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother.1997, 41(10): 2127–2131.
[16] D L Shinabarger, K R Marotti, R W Murray, A H Lin. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother, 1997, 41(10): 2132–2136.
[17] Gonzales RD, Schreckenberger PC, Graham MB, et a1. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid [J]. Lancet, 2001, 357: 1179.
[18] Stevens D, Smith L G, Bruss J B, et al. Randomized comparison of linezolid (PUN-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissues infection[J]. Antimicrob Agents Chemother, 2000, 44(12): 3408 -3413.
[19] Patal U, Yan YP, Hobbs F, et al. Oxazolidinones mechanism of action: inhibition of the first peptide bond formation [J]. J Biol Chem, 2001, 276(40): 37199.
[20] Bobkova EV, Yan YP, Jordan DB, et al. Catalytic properties of mutant 23S ribosomes resistant to oxazolidinones[J]. J Biol Chem, 2003, 278: 9802.
[21] Aoki H, Dekany K, Adams SL, et al. The gene encoding the elongation factor P protein is essential for viability and is required for protein synthesis[J]. J Biol Chem, 1997, 272: 32254.
[22] Jackson B. Hester, Steven Joseph Brickner, Michael Robert Barbaehyn, et al. 5-amidomethylα,β-saturated and–unsaturated 3-arylbutyrolactone antibacterial agents. US5708169.
[23] S·库迪斯,E·巴奥曼,W·冯德恩,作为除草剂的3-(4,5-二氢异噁唑-3-基)-取代的苯甲酰基吡唑,中国专利,00816533.5。
[24]周宇涵,苗蔚荣,取代苯基五元氮杂环类除草剂,02143654.1,2005-12-28。
[25]柳应杰,金亨来,田东柱,等。除草的5-苄氧基甲基-1,2-异噁唑啉衍生物。01815140.X,2007-03-07。
[26] S·库迪斯,E·巴奥曼,W·冯德恩,环丙基稠合的3-(4,5-二氢异噁唑-3-基)-取代的苯甲酰基吡唑,00816531.9。
[27]中谷昌央,久语良太郎,宫崎雅弘,异噁唑啉衍生物和含有它们作为活性组分的除草剂,ZL02804675.7,2006-05-31。
[28] B·西弗尼克,M·兰德斯,E·基布勒,等。具有增效效果的除草混合物,200410057587.6。
[29] E·哈克,H·比林格,H·P·胡夫,含有特殊的磺酰脲的除草组合物,02814550.X。
[30] O·瓦格纳,M·雷克,M·维切尔,等。用作除草剂的3-杂芳基取代的5-甲氧基甲基异噁唑啉,03809304.9。
[31]中谷昌央,久语良太郎,宫崎雅弘,等。异噁唑啉衍生物和含有它们作为活性组分的除草剂。200510066670.4。
[32]王正权。取代苯基异噁唑类除草剂。200510119757.3。
[33] M·布兰兹,S·尼科利克,P·埃肯伯格。用于病毒性疾病的药物。01805765.9。
[34]原田真宏,武田顺子,中村年男。取代的异噁唑基噻吩化合物。99811631.9。
[35] J·I·安德雷斯-吉尔。作为抗抑郁药的异噁唑啉衍生物。02805243.9。
[36]张田林,庄昌龙,胡卫东。异噁唑醚菊酯杀虫剂制备方法。01133201.8。
[37] R·布劳恩,O·奥尔特,K-J·哈克。芳基异噁唑啉衍生物其制备方法及其作为杀虫剂的用途。02807065.8。
[38] A·普托克,E·阿默曼,R·施蒂尔勒。杀真菌混合物。02803673.5。
[39] K·艾肯,A·普托克,E·阿默曼。基于酰胺化合物的杀真菌混合物。01820787.1。
[40] B·穆勒,A·普托克,E·阿默曼。杀真菌混合物。01820789.8。
[41] A·普托克,E·阿默曼,R·施蒂尔勒。杀真菌混合物。02803782.0。
[42]三谷滋,蒲池健,山口朋奈,等。植物病原菌防治用组合物以及植物病原菌的防治方法。ZL 02815107.0,2006-04-05。
[43]刘长令;李淼;张弘。异噁唑类化合物作为杀菌剂的应用。200510047152.8。
[44] M. Barbachyn, J. Morris, WO. Pat. 9,941,244 (1999).
[45] Fukuda Y, Hammond ML. Bicyclo [3,1,0] hexane-containing oxazolidinone antibiotics and derivatives thereof [P]. WO: 03027083, 2003-04-03.
[46] Weidner—Wells MA, Boggs CM, Foleno BD, et a1. Novel piperidinyloxy oxazohdinone an timicrobial agents [J]. Bioorg Med Chem Lett, 2001, 11(14): 1829-1832.
[47] Park CH, Bfittdli DR. Antibacterials synthesis and structure-activity studies of 3-aryl-2-oxazolidones.4.multiply-substituted aryl derivatives[J]. J. Med. Chem., 1992, 35(6): 1156
[48] Gregory WA, BritteUi DR, Wang CL, et al. Antibacterials synthesis and structure-activity studies of 3-aryl-2-oxooxazolidinones[J]. J. Med. Chem., 1989, 32(8): 1673.
[49] Albrecht HA, Beskid G, Chan KK, et al, Cephalosporin 3-quinolone esters with a dual mode of action. J Med Chem, 1990, 33: 77-83.
[50]韩莹,屠树滋,周卫芬,等。香豆素磺酰脲类化合物的合成及其降血糖活性研究[J]。中国药科大学学报,2002,33(2):93—97。
[51]张雷,张万年,周有骏等。三氮唑苄胺类化合物的合成及其抗真菌活性[J]。第二军医大学学报,2000,21(2):149—152.
[52]白宝清,袁牧,周欣。1-(2,3-二甲基苯基)哌嗪的合成。广州医学院学报。2007,35(1):54-56。
[53]李宁蔚,朱泉。1-(2,3-二氯苯基)哌嗪的合成研究。天津化工,2006,20(2):24-27。
[54]徐应淑,袁牧,黎刚。1-(3-甲氧苯基)哌嗪的合成及结构研究。遵义医学院学报,2005,28(1):7-8。
[55]童国通,卢孔燎。1-(4-甲氧基苯基)-4-(4-氨基苯基)哌嗪的合成。精细化工中间体,2003,33(6):34-36。
[56]唐龙骞,孟昭力,赵彦伟。N-(4,4′-二氟苯甲基)哌嗪的合成。中国医药工业杂志,2004,35(6):331。
[57] Drain DJ, Goodacre CL, Seymour DE. P-aminosalicylic acid.Ⅲ. Studies on in vitro tuberculostatic behavior of p-aminosalicylic acid and related compounds [J]. J Pharm Pharmacol, 1949, 1: 784-787.
[58] Jones DH, Slack R, Squires S, et al. Antiviral chemotherapy.Ⅰ.The activity of pyridine and quinolinone derivatives against nerovaccina in mice[J]. J Med Chem, 1965, 8(5): 676-680.
[59] Wilson HR, Revankar GR, Tolman RL. In vivo activity of certain thiosemicarbazone against trypanosome cruzi [J]. J Med Chem, 1974, 17(7): 760-761.
[60] Lin LF, Lee SJ, Chen CT. Studies on potential antitumor agents. (Ⅱ). Thiosemicarbazones of p-bromophenyl and o-chlorophenylpyridine-2-carbo - -xaldehydes [J]. Heterocycles, 1977, 7(1): 347-352.
[61]胡惟孝,孙楠,杨忠愚。缩氨基硫脲类化合物的合成及其抗癌活性研究。高等学校化学学报,2001,22(12): 2014-2017.
[62]胡惟孝,孙楠,杨忠愚。缩氨基硫脲类化合物的合成及其抗癌活性研究。中国药物化学杂志,2001, 11(3): 129-133。
[63]周守明,金昱泰。新型缩氨基硫脲化合物的合成及其抗癌活性的研究。核化学与放射化学,1999, 21(4): 233-238。
[64]孟歌,棘丽君,刘培杰。缩氨基硫脲及其环化产物噻二唑的合成及其活性。化学研究,1999,10(2):51-53。
[65] Curdev Singh HKP. Antifungal activity of metal complexes of thiosemicarbazones. Inorg. Chem. Acta., 1985, 108:87.
[66] Dobek A.S., Klaman DL., Dickson ET, et al. Inhibition of clinically significant bacterial organism in vitro by 2-acetylpyridine thiosemicarbazone. Antimicro Agents Chemother, 1980, 18: 27.
[67] Mohan M, Kumar M., Kumar A, et al. Synthesis, charoterizatioa and antitumor activity of iron () and iron () complexes of N-heterocyclic carboxaldehyde thiosemicarbazones. J inorg biochem, 1988, 32:239.
[68] Shukla HK. Desai NC, Astik RR, et al. studies on some thiosemicarbazones and 1,3,4-thiadiazolines as potential antitubercular and antibacterial agents. J Indian Chem Soc, 1984, 21: 168.
[69]万嵘,汪海波。马来酸替加色罗的合成工艺改进。中国药物化学杂志,2003,(13)1:40～41。
[70] Kari-Heinz Buchheit, Rainer Gamse, Rudolf Giger, et a1.The serotonin 5-HT4 receptor. 2. structure-activity studies of the indole carbazimidamide class of agonists [J]. J Med Chem, 1995, 38(13): 2331-2338.
[71] Klayman DL, Bartosevich JF, Joseph F, et al. 2-Acetylpyridine thiosemicarbazones. A new class of potential antimalarial agents [J]. J Med Chem, 1979, 22(7): 855-862.
[72]段建忖,唐红霞。1,2,4-三氮唑粪杀菌剂的研究进展。河南化工,2002(6):6-8。
[73]杨光富。麦角甾醇生物合成抑制剂分子设计的研究进展[J]。农药译丛,1996,(1):21。
[74]杜英娟。国外杀茵剂发展近况[J]。农药,1989,(1): 48。
[75]梁诚。含氟医药的合成技术与生产现状。中国医药情报,2003, 9(2): 13。
[76] Lui Norbert, Panskus Hans, Muller Herbert. Process for preparing quinolone-and naphthyridone-carboxylic acids and esters thereof. [P]. US 62290l7.
[77]顾海宁,蒋永祥,葛海泉。左旋氧氟沙星合成的新工艺研究。高校化学工程学报,2005,l9(5): 708-711。
[78]田孟超,屈凌波,谢建刚等。1-烷基-6-氟-1,4-二氢-7-(4-酰基-1-哌嗪基)-4-氧代喹啉-3-羧酸类似物的合成及其抗菌活性。中国药物化学杂志,2002,12(5):249-253。
[79]李英俊,刘素娜,许永廷等。1-环丙基-6-氟-7-(4-酰基-1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸的合成及其抗菌活性研究。有机化学,2005,25(10):1221~1226。
[80]胡国强,孙茂峰,谢松强等。3-(4-哌嗪-1-苯基)-6-取代-S-三唑并[3,4-b][1,3,4]噻二唑盐酸盐的合成及抗菌活性。药学学报,2007,42(1):54—57。
[81]袁胜群。巴洛沙星的合成研究。生物加工过程,2007,5(1):74-77。
[82]徐明。口服三氮唑核苷治疗扁平疣1例。中华综合医学杂志,2001,2(7):670。
[83]曾明华等。有发展前途的三氮唑类杀菌剂。化工文摘,2001,8:56。
[84]楚勇,吕丁,徐鸣夏等。新型三氮唑醇类抗真菌药物合成。中国药物化学杂志,2001,11(2):80-84。
[85]李振霞,杨秋艳,蒲仁庆等。三氮唑核苷与抗菌药物联合治疗急性气管-支气管炎疗效观察。临床医学,2002,22(3):47。
[86]李德江,马文展。三氮唑类抗真菌剂的研究进展。天津化工,2002,5:27-28。
[87]张红,白东鲁。抗真菌药物的研究进展[J]。中国药物化学杂志,1997,7(4):303—310。
[88] Rex JH, Rinaldi MG, Pfaller MA. Resistance of candida species to fluconazole [J]. Antimicrobial Agents & Chemotherapy, 1995, 39(1): l-8.
[89] Naito T, Hata K, Tsumoda A. ER-30346 triazole antifungal[J]. Drugs of the Future, 1996, 21(1): 20-24.
[90] Prorntling RA, Castaner J. Voriconazole[J]. Drugs of the Future, 1996, 21(3): 266-271.
[91]甘亚,吕丁。三氮唑醇类化合物的合成及抗真菌活性[J]。中国药物化学杂志,2001,4(2):85—90。
[92]谢剑华,李光华。抗真菌剂三氮唑含硫化合物的合成[J]。中国药物化学杂志,1997,7(3):180—184。
[93]吴义杰,周旭。三唑类化合物的合成及抗真菌活性[J]。中国药物化学杂志,1998,8(3):235—238。
[94]吴义杰,杨济秋。三唑类化合物的合成及抗真菌活性[J]。中国药物化学杂志,1999,9(3):176—180。
[95]刘滔。新抗真菌剂三氮唑丙醇类含氮衍生物的合成。中国药物化学杂志,2002,12(6):333-336。
[96]潘建林,陶兰,幸勇,等。N-苯基哌嗪的合成[J]。中国现代应用药学杂志,2001,18(5):372—374。
[97] Pollard CB. Derivatves of piperation, synthesis of piperazine and substituted piperazine[J]. J Chem Soc, 1958, 13(6): 812—814.
[98]王伟,肖国民。1-甲基-3一苯基哌嗪的合成[J]。精细化工,2004,21(9):711—713.
[99]童国通,卢孔燎.1-(4-甲氧基苯基)-4-(4-氨基苯基)哌嗪的合成[J].精细化工中间体,2003,33(6):34—35,45。
[100] Chen X, Wang L, Zhao ZZ. Synthesis of 1-(3-phthalimideo-2-oxobuty1)- 4-substitutenyl—piperazines and their anti-HIV reverse transcriptase activity[J]. Acta Pharm Sin, 2002, 37(5): 343—347.
[101]何欣,林紫云,朱莉亚。肉桂酰胺及α-苯基肉桂酰胺衍生物的合成及扩血管活性[J]。药学学报,1999,34(3):192-196。
[102] Yingjie Cui, Yushe Yang, Kaixian Chen, et al. Synthesis and Antibacterial Activity of Oxazolidinone Containing Sulphonyl Group. Bioorganic & Medicinal Chemistry Letters, 2003, 13: 2311–2313.
[103]徐淑云,卞如濂,陈修。药理学实验方法。人民卫生出版社,2002。
[104]余德胜,王志谦,熊莺,等。利奈唑酮合成新工艺。中国药物化学杂志,2005, 15(2): 89-91.
[105]孟庆国,刘浚。利奈唑酮的合成工艺改进。中国药物化学杂志,2003, 13(1): 28-30.
[106]孟庆国,金洁,刘浚。利奈唑酮的合成。中国新药杂志,2002,11(5): 387-380.。
[2]雷连成.中国兽药杂志,2002,36(11):41-44。
[3]张国强,钱卫东,张立昌等,克服细菌耐药性的新药及其临床应用,国外畜牧学—猪与禽,2003,23(1):60-61。
[4]尤启冬,药物化学,化学工业出版社,北京,2004。
[5] A.M. Slee, M. A. Wuonola, R. J. McRipley,etal. Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrob.Agents Chemother., 1987, 31, 1791.
[6] Gonzales RD, Schreckenberger PC, Graham MB, et a1. Infections due to vancomycin-resistance Enterococcus faecium resistance to linezolid [J]. Lancet, 2001, 357 (9263): 1179.
[7] Nilius AM. Have the oxazolidinones lived up to their billing? Future perspectives for this antibacterial class [J]. Current Opinion Invest Drugs, 2003, 4(2): 149-155.
[8] Daly JS, Eliopoulos GM, Reiszner, et a1. Activity and mechanism of action of DuP105 and DuP721, new oxazolidinone compounds [J]. J Antimicrob Chemother, 1988, 21(6): 721-730.
[9] Slee AM, Wuonola MA, Mcripley RJ, et al. Oxazolidinones, a new class of synthetic antibacterial agent: in vitro and in vivo activities of DuP105 and DuP721 [J]. Antimicrob Agents Chemother, 1987, 31(11): 1791-1797.
[10] Kaatz GW, Seo SM. In vitro activities of oxazolidinone compounds U-100592 and U-100766 against Staphylococcus aureus and Staphylococcus epidermidis [J]. Antimicrob Agents Chemother, 1996, 40(3): 799-801.
[11] Kloss, P., Xiong, L., Shinabarger, D. and Mankin, A.S. Resistance mutations in 23S rRNA identify the site of action of protein synthesis inhibitor, linezolid, in the ribosomal peptidyl transferase center. J. Mol. Biol., 1999, 294(2): 93-101.
[12]陈代杰。抗菌药物与细菌耐药性。华东理工大学出版社。2001年第一版。
[13] Clemett D, Markham A. Linezolid [J]. Drugs Fut, 2000, 59(4) : 815-827.
[14] Fines M, Leclercq R. Activity of linezolid against Gram-positive cocci possessing genes conferring resistance to protein synthesis inhibitors. Antimicrob Chemother, 2000, 45(4): 797.
[15] A H Lin, R W Murray, T J Vidmar, and K R Marotti. The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother.1997, 41(10): 2127–2131.
[16] D L Shinabarger, K R Marotti, R W Murray, A H Lin. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother, 1997, 41(10): 2132–2136.
[17] Gonzales RD, Schreckenberger PC, Graham MB, et a1. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid [J]. Lancet, 2001, 357: 1179.
[18] Stevens D, Smith L G, Bruss J B, et al. Randomized comparison of linezolid (PUN-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissues infection[J]. Antimicrob Agents Chemother, 2000, 44(12): 3408 -3413.
[19] Patal U, Yan YP, Hobbs F, et al. Oxazolidinones mechanism of action: inhibition of the first peptide bond formation [J]. J Biol Chem, 2001, 276(40): 37199.
[20] Bobkova EV, Yan YP, Jordan DB, et al. Catalytic properties of mutant 23S ribosomes resistant to oxazolidinones[J]. J Biol Chem, 2003, 278: 9802.
[21] Aoki H, Dekany K, Adams SL, et al. The gene encoding the elongation factor P protein is essential for viability and is required for protein synthesis[J]. J Biol Chem, 1997, 272: 32254.
[22] Jackson B. Hester, Steven Joseph Brickner, Michael Robert Barbaehyn, et al. 5-amidomethylα,β-saturated and–unsaturated 3-arylbutyrolactone antibacterial agents. US5708169.
[23] S·库迪斯,E·巴奥曼,W·冯德恩,作为除草剂的3-(4,5-二氢异噁唑-3-基)-取代的苯甲酰基吡唑,中国专利,00816533.5。
[24]周宇涵,苗蔚荣,取代苯基五元氮杂环类除草剂,02143654.1,2005-12-28。
[25]柳应杰,金亨来,田东柱,等。除草的5-苄氧基甲基-1,2-异噁唑啉衍生物。01815140.X,2007-03-07。
[26] S·库迪斯,E·巴奥曼,W·冯德恩,环丙基稠合的3-(4,5-二氢异噁唑-3-基)-取代的苯甲酰基吡唑,00816531.9。
[27]中谷昌央,久语良太郎,宫崎雅弘,异噁唑啉衍生物和含有它们作为活性组分的除草剂,ZL02804675.7,2006-05-31。
[28] B·西弗尼克,M·兰德斯,E·基布勒,等。具有增效效果的除草混合物,200410057587.6。
[29] E·哈克,H·比林格,H·P·胡夫,含有特殊的磺酰脲的除草组合物,02814550.X。
[30] O·瓦格纳,M·雷克,M·维切尔,等。用作除草剂的3-杂芳基取代的5-甲氧基甲基异噁唑啉,03809304.9。
[31]中谷昌央,久语良太郎,宫崎雅弘,等。异噁唑啉衍生物和含有它们作为活性组分的除草剂。200510066670.4。
[32]王正权。取代苯基异噁唑类除草剂。200510119757.3。
[33] M·布兰兹,S·尼科利克,P·埃肯伯格。用于病毒性疾病的药物。01805765.9。
[34]原田真宏,武田顺子,中村年男。取代的异噁唑基噻吩化合物。99811631.9。
[35] J·I·安德雷斯-吉尔。作为抗抑郁药的异噁唑啉衍生物。02805243.9。
[36]张田林,庄昌龙,胡卫东。异噁唑醚菊酯杀虫剂制备方法。01133201.8。
[37] R·布劳恩,O·奥尔特,K-J·哈克。芳基异噁唑啉衍生物其制备方法及其作为杀虫剂的用途。02807065.8。
[38] A·普托克,E·阿默曼,R·施蒂尔勒。杀真菌混合物。02803673.5。
[39] K·艾肯,A·普托克,E·阿默曼。基于酰胺化合物的杀真菌混合物。01820787.1。
[40] B·穆勒,A·普托克,E·阿默曼。杀真菌混合物。01820789.8。
[41] A·普托克,E·阿默曼,R·施蒂尔勒。杀真菌混合物。02803782.0。
[42]三谷滋,蒲池健,山口朋奈,等。植物病原菌防治用组合物以及植物病原菌的防治方法。ZL 02815107.0,2006-04-05。
[43]刘长令;李淼;张弘。异噁唑类化合物作为杀菌剂的应用。200510047152.8。
[44] M. Barbachyn, J. Morris, WO. Pat. 9,941,244 (1999).
[45] Fukuda Y, Hammond ML. Bicyclo [3,1,0] hexane-containing oxazolidinone antibiotics and derivatives thereof [P]. WO: 03027083, 2003-04-03.
[46] Weidner—Wells MA, Boggs CM, Foleno BD, et a1. Novel piperidinyloxy oxazohdinone an timicrobial agents [J]. Bioorg Med Chem Lett, 2001, 11(14): 1829-1832.
[47] Park CH, Bfittdli DR. Antibacterials synthesis and structure-activity studies of 3-aryl-2-oxazolidones.4.multiply-substituted aryl derivatives[J]. J. Med. Chem., 1992, 35(6): 1156
[48] Gregory WA, BritteUi DR, Wang CL, et al. Antibacterials synthesis and structure-activity studies of 3-aryl-2-oxooxazolidinones[J]. J. Med. Chem., 1989, 32(8): 1673.
[49] Albrecht HA, Beskid G, Chan KK, et al, Cephalosporin 3-quinolone esters with a dual mode of action. J Med Chem, 1990, 33: 77-83.
[50]韩莹,屠树滋,周卫芬,等。香豆素磺酰脲类化合物的合成及其降血糖活性研究[J]。中国药科大学学报,2002,33(2):93—97。
[51]张雷,张万年,周有骏等。三氮唑苄胺类化合物的合成及其抗真菌活性[J]。第二军医大学学报,2000,21(2):149—152.
[52]白宝清,袁牧,周欣。1-(2,3-二甲基苯基)哌嗪的合成。广州医学院学报。2007,35(1):54-56。
[53]李宁蔚,朱泉。1-(2,3-二氯苯基)哌嗪的合成研究。天津化工,2006,20(2):24-27。
[54]徐应淑,袁牧,黎刚。1-(3-甲氧苯基)哌嗪的合成及结构研究。遵义医学院学报,2005,28(1):7-8。
[55]童国通,卢孔燎。1-(4-甲氧基苯基)-4-(4-氨基苯基)哌嗪的合成。精细化工中间体,2003,33(6):34-36。
[56]唐龙骞,孟昭力,赵彦伟。N-(4,4′-二氟苯甲基)哌嗪的合成。中国医药工业杂志,2004,35(6):331。
[57] Drain DJ, Goodacre CL, Seymour DE. P-aminosalicylic acid.Ⅲ. Studies on in vitro tuberculostatic behavior of p-aminosalicylic acid and related compounds [J]. J Pharm Pharmacol, 1949, 1: 784-787.
[58] Jones DH, Slack R, Squires S, et al. Antiviral chemotherapy.Ⅰ.The activity of pyridine and quinolinone derivatives against nerovaccina in mice[J]. J Med Chem, 1965, 8(5): 676-680.
[59] Wilson HR, Revankar GR, Tolman RL. In vivo activity of certain thiosemicarbazone against trypanosome cruzi [J]. J Med Chem, 1974, 17(7): 760-761.
[60] Lin LF, Lee SJ, Chen CT. Studies on potential antitumor agents. (Ⅱ). Thiosemicarbazones of p-bromophenyl and o-chlorophenylpyridine-2-carbo - -xaldehydes [J]. Heterocycles, 1977, 7(1): 347-352.
[61]胡惟孝,孙楠,杨忠愚。缩氨基硫脲类化合物的合成及其抗癌活性研究。高等学校化学学报,2001,22(12): 2014-2017.
[62]胡惟孝,孙楠,杨忠愚。缩氨基硫脲类化合物的合成及其抗癌活性研究。中国药物化学杂志,2001, 11(3): 129-133。
[63]周守明,金昱泰。新型缩氨基硫脲化合物的合成及其抗癌活性的研究。核化学与放射化学,1999, 21(4): 233-238。
[64]孟歌,棘丽君,刘培杰。缩氨基硫脲及其环化产物噻二唑的合成及其活性。化学研究,1999,10(2):51-53。
[65] Curdev Singh HKP. Antifungal activity of metal complexes of thiosemicarbazones. Inorg. Chem. Acta., 1985, 108:87.
[66] Dobek A.S., Klaman DL., Dickson ET, et al. Inhibition of clinically significant bacterial organism in vitro by 2-acetylpyridine thiosemicarbazone. Antimicro Agents Chemother, 1980, 18: 27.
[67] Mohan M, Kumar M., Kumar A, et al. Synthesis, charoterizatioa and antitumor activity of iron () and iron () complexes of N-heterocyclic carboxaldehyde thiosemicarbazones. J inorg biochem, 1988, 32:239.
[68] Shukla HK. Desai NC, Astik RR, et al. studies on some thiosemicarbazones and 1,3,4-thiadiazolines as potential antitubercular and antibacterial agents. J Indian Chem Soc, 1984, 21: 168.
[69]万嵘,汪海波。马来酸替加色罗的合成工艺改进。中国药物化学杂志,2003,(13)1:40～41。
[70] Kari-Heinz Buchheit, Rainer Gamse, Rudolf Giger, et a1.The serotonin 5-HT4 receptor. 2. structure-activity studies of the indole carbazimidamide class of agonists [J]. J Med Chem, 1995, 38(13): 2331-2338.
[71] Klayman DL, Bartosevich JF, Joseph F, et al. 2-Acetylpyridine thiosemicarbazones. A new class of potential antimalarial agents [J]. J Med Chem, 1979, 22(7): 855-862.
[72]段建忖,唐红霞。1,2,4-三氮唑粪杀菌剂的研究进展。河南化工,2002(6):6-8。
[73]杨光富。麦角甾醇生物合成抑制剂分子设计的研究进展[J]。农药译丛,1996,(1):21。
[74]杜英娟。国外杀茵剂发展近况[J]。农药,1989,(1): 48。
[75]梁诚。含氟医药的合成技术与生产现状。中国医药情报,2003, 9(2): 13。
[76] Lui Norbert, Panskus Hans, Muller Herbert. Process for preparing quinolone-and naphthyridone-carboxylic acids and esters thereof. [P]. US 62290l7.
[77]顾海宁,蒋永祥,葛海泉。左旋氧氟沙星合成的新工艺研究。高校化学工程学报,2005,l9(5): 708-711。
[78]田孟超,屈凌波,谢建刚等。1-烷基-6-氟-1,4-二氢-7-(4-酰基-1-哌嗪基)-4-氧代喹啉-3-羧酸类似物的合成及其抗菌活性。中国药物化学杂志,2002,12(5):249-253。
[79]李英俊,刘素娜,许永廷等。1-环丙基-6-氟-7-(4-酰基-1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸的合成及其抗菌活性研究。有机化学,2005,25(10):1221~1226。
[80]胡国强,孙茂峰,谢松强等。3-(4-哌嗪-1-苯基)-6-取代-S-三唑并[3,4-b][1,3,4]噻二唑盐酸盐的合成及抗菌活性。药学学报,2007,42(1):54—57。
[81]袁胜群。巴洛沙星的合成研究。生物加工过程,2007,5(1):74-77。
[82]徐明。口服三氮唑核苷治疗扁平疣1例。中华综合医学杂志,2001,2(7):670。
[83]曾明华等。有发展前途的三氮唑类杀菌剂。化工文摘,2001,8:56。
[84]楚勇,吕丁,徐鸣夏等。新型三氮唑醇类抗真菌药物合成。中国药物化学杂志,2001,11(2):80-84。
[85]李振霞,杨秋艳,蒲仁庆等。三氮唑核苷与抗菌药物联合治疗急性气管-支气管炎疗效观察。临床医学,2002,22(3):47。
[86]李德江,马文展。三氮唑类抗真菌剂的研究进展。天津化工,2002,5:27-28。
[87]张红,白东鲁。抗真菌药物的研究进展[J]。中国药物化学杂志,1997,7(4):303—310。
[88] Rex JH, Rinaldi MG, Pfaller MA. Resistance of candida species to fluconazole [J]. Antimicrobial Agents & Chemotherapy, 1995, 39(1): l-8.
[89] Naito T, Hata K, Tsumoda A. ER-30346 triazole antifungal[J]. Drugs of the Future, 1996, 21(1): 20-24.
[90] Prorntling RA, Castaner J. Voriconazole[J]. Drugs of the Future, 1996, 21(3): 266-271.
[91]甘亚,吕丁。三氮唑醇类化合物的合成及抗真菌活性[J]。中国药物化学杂志,2001,4(2):85—90。
[92]谢剑华,李光华。抗真菌剂三氮唑含硫化合物的合成[J]。中国药物化学杂志,1997,7(3):180—184。
[93]吴义杰,周旭。三唑类化合物的合成及抗真菌活性[J]。中国药物化学杂志,1998,8(3):235—238。
[94]吴义杰,杨济秋。三唑类化合物的合成及抗真菌活性[J]。中国药物化学杂志,1999,9(3):176—180。
[95]刘滔。新抗真菌剂三氮唑丙醇类含氮衍生物的合成。中国药物化学杂志,2002,12(6):333-336。
[96]潘建林,陶兰,幸勇,等。N-苯基哌嗪的合成[J]。中国现代应用药学杂志,2001,18(5):372—374。
[97] Pollard CB. Derivatves of piperation, synthesis of piperazine and substituted piperazine[J]. J Chem Soc, 1958, 13(6): 812—814.
[98]王伟,肖国民。1-甲基-3一苯基哌嗪的合成[J]。精细化工,2004,21(9):711—713.
[99]童国通,卢孔燎.1-(4-甲氧基苯基)-4-(4-氨基苯基)哌嗪的合成[J].精细化工中间体,2003,33(6):34—35,45。
[100] Chen X, Wang L, Zhao ZZ. Synthesis of 1-(3-phthalimideo-2-oxobuty1)- 4-substitutenyl—piperazines and their anti-HIV reverse transcriptase activity[J]. Acta Pharm Sin, 2002, 37(5): 343—347.
[101]何欣,林紫云,朱莉亚。肉桂酰胺及α-苯基肉桂酰胺衍生物的合成及扩血管活性[J]。药学学报,1999,34(3):192-196。
[102] Yingjie Cui, Yushe Yang, Kaixian Chen, et al. Synthesis and Antibacterial Activity of Oxazolidinone Containing Sulphonyl Group. Bioorganic & Medicinal Chemistry Letters, 2003, 13: 2311–2313.
[103]徐淑云,卞如濂,陈修。药理学实验方法。人民卫生出版社,2002。
[104]余德胜,王志谦,熊莺,等。利奈唑酮合成新工艺。中国药物化学杂志,2005, 15(2): 89-91.
[105]孟庆国,刘浚。利奈唑酮的合成工艺改进。中国药物化学杂志,2003, 13(1): 28-30.
[106]孟庆国,金洁,刘浚。利奈唑酮的合成。中国新药杂志,2002,11(5): 387-380.。