氟喹诺酮从抗菌药到降血脂新药的发现

1、氟喹诺酮:从抗菌药到降血脂新药的发现 第六届世界农药科技与应用发展学术交流会心血管疾病概况u全球每年1200-1600万人死于心血管病和脑中风u高血脂症引起的动脉粥样硬化是造成冠心病，高血压和脑血管疾病的主要原因u我国高血脂症的患者超过7500万，随人口老龄化的严重，患者还在增加u降血脂药物已成为全球第一类畅销药物u高血脂：胆固醇，甘油三酯脂蛋白分类u乳糜微粒(CM) d1.063， HDL越高，动脉粥样硬化风险越小降血脂药物的分类u3-羟基-3-甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂（他汀），占降血脂药物市场的90以上，作用于胆固醇的合成，明显降低LDL u胆固醇吸收抑制剂：依替米贝

2、 u纤维酸衍生物，“贝特”，降TG，升HDLu胆酸螯合剂：离子交换树脂 u烟酸 上市的他汀药物HCH3CH3OOOOHOCH3CH3HCH3CH3OOOOHOCH3CH3CH3HCH3OHOOCH3CH3OHNa+COOOHNa+COOOHNCH3CH3OHFlovastatinsimvastatinpravastatin sodiumfluvastatin sodiumRRRRRRSRNFONHCH3CH3OHCOOOH OHNNFCH3CH3NCH3SOOCH3COOOH NOHFCOOOH Ca2+Ca2+Ca2+222atorvastatin calciumrosuvastatin c

3、alciumpitavastatin calciumSRSRRR阿托伐他汀:best in class年份年份销售额（亿美元）销售额（亿美元）19971997上市上市1998199818 18 1999199940402000200050502001200164642002200279 79 20032003103 103 20042004108 108 20052005121 121 2006200613613620072007135135200820081371372009200912312320102010129129201120111251252012201239.4539.45他汀类

4、药物作用机制OCH2SCoAOHCH3CH2COOHCH2OHCH3CH2CH2OHCOOHOHCH3CH3CH3CH3CH3NADPHCoASHNADPHMG CoAMevalonate+他汀类药物构效关系HCH3CH3OOOOHOCH3CH3HCH3CH3OOOOHOCH3CH3CH3HCH3OHOOCH3CH3OHNa+COOOHNa+COOOHNCH3CH3OHFlovastatinsimvastatinpravastatin sodiumfluvastatin sodiumRRRRRRSRNFONHCH3CH3OHCOOOH OHNNFCH3CH3NCH3SOOCH3COOOH NO

5、HFCOOOH Ca2+Ca2+Ca2+222atorvastatin calciumrosuvastatin calciumpitavastatin calciumSRSRRROHCOOMOH连 接 链母环侧链的结构改造侧链的结构改造u3,5-二羟基戊酸或内酯是药效团，手性碳原子3R,5S(碳链为双键)，3R,5R (碳链为单键)u氟伐他汀为顺式异构体，(3R,5S)有药理活性，(3S,5R)无药理活性，其它药物为单一异构体u开环羧酸的活性优于内酯OHOHCOOMOOOH碳链母环碳链母环12345连接链的结构改造连接链的结构改造u必须两个碳，增加或减少活性下降uCH2CH2, CH=CH,

6、有活性uCC或OCH2没有活性uCH=CH，trans-活性优于cis-活性O H O HC O O M碳链母 环母环:六氢萘不是必需基团u全合成他汀：吲哚,吡咯,嘧啶,喹啉u药核基团的两个邻位有对氟苯基和异丙基或环丙基HCH3CH3OOOOHOCH3CH3NCH3CH3OOOHFOHNa+NFONHCH3CH3OOOHOHOOOHOHNNFCH3CH3NCH3SOOCH3NOOOHOHF药物作用的选择性u特异性毒性：横纹肌u肝脏是药效的靶器官，药物进入肝脏有主动转运机制u药物进入肌细胞靠被动扩散u高亲脂性有利于被动扩散u肝选择性：合适的亲脂性/亲水性，通过母环的结构修饰实现氟喹诺酮抗菌药的发

7、现历史氟喹诺酮:6位引入F,可显著提高对DNA促旋酶的抑制作用和体外抗菌作用NNHCH(CH2)3N(C2H5)2CH3ClStructural modificationNNC2H5CO2HOH3CchloroquineantimalarialNNNOCO2HC2H5NHNNOCO2HC2H5NHNFgeneration 1pipemidic acid generation 2nalidixic acid 19611974 nofloxacin generation 31979上市药物上市药物 22个：诺氟沙星，培氟沙星，环丙沙星，氧氟沙星，依诺沙星，洛美沙星，托氟沙星，氟罗沙星，卢氟沙星，那

8、氟沙星，左氟沙星，司氟沙星，曲伐沙星，加替沙星，莫西沙星，帕珠沙星，吉米沙星，巴洛沙星，普利沙星，加雷沙星，西他沙星，安妥沙星 兽药6个：达诺沙星，二氟沙星，恩氟沙星，麻保沙星，奥比沙星，沙拉沙星 本课题组对氟喹诺酮的结构改造氟喹诺酮环的亲核取代反应(SNAR)Zhenfa Zhang, Weicheng Zhou. Tetrahedron Lett 2005,46:3855Zhenfa zhang, Weicheng Zhou, Aizhen Yu. Bioorg Med Chem Lett 2004,14:393Zhenfa Zhang, Aizhen Yu, Weicheng Zhou.

9、 Bioorg Med Chem 2007, 15:7274张贞发，周伟澄. 中国医药工业杂志 2002,33:209NOR1FR7R8CO2EtNOR1FO2NCH2R8CO2EtCH3NO2R1=Et, cyclopropanylR7=F, ClR8=F, HNOR1FOHCR8CO2EtKMnO4本课题组对氟喹诺酮SNAR的研究NOCO2HRFFFNOCO2HRFSPhFNOCO2HRFPhSSPhNOCO2HRPhSPhSSPhPhSHNaH, DMSO RTPhSH, NaHDMSO 50oC2N KOH, 50oCH2OPhOHNaH, DMSO60oCNORCO2HFPhOOPh

10、NORCO2HFPhOFNORCO2HPhOPhOOPhPhOHNaH, DMSO, RT PhOH, NaHDMSO, 140oCXiang Ma, Weicheng Zhou, Reto Brun. Bioorg Med Chem Lett 2009,19:986本课题组对氟喹诺酮SNAR的研究Zhengyan Cai, Weicheng Zhou, Lixin Sun. Bioorg Med Chem 2007, 15:7809Zhengyan Cai, Weicheng Zhou, Luyong Zhang. J Chin Pharm Sci 2010, 19:15Qun Hao, Z

11、hengyan Cai, Weicheng Zhou. Chem Biol Drug Des 2011, 78:730NFFFClCO2EtAr-OHTHF, NaH, NFFFO-ArCO2EtAr-OHDMF, NaH,NFFOO-ArCO2EtArOArOArOArNO-ArCO2EtOArNFOO-ArCO2EtArAr-OHAr-OHAr-SHTHF, Et3N, NFFFS-ArCO2EtAr-SHTHF, Et3N, rtAr-SHDMF, K2CO3,NFFSS-ArCO2EtArSArSArSArNS-ArCO2EtSArNFSS-ArCO2EtArAr-SHDMF, K2C

12、O3, rt-100oC1 equv.2 equv.40oCK2CO3, DMSO, 90oCK2CO3, DMF, 60oC-25oC60oC1 equv.2 equv.33.3 equv.4.5 equv.33.3 equv.4.5 equv.本课题组对氟喹诺酮SNAR的研究Shikui Zhao, Weicheng Zhou, Jun Liu. Bioorg Med Chem 2009, 17:7915Shikui Zhao, Weicheng Zhou. Syn Commun 2011, 41:20NFFClCO2EtAr-NHCH3THF, BuLi, N实现肝选择性，通过母环的结构

13、修饰合适的亲脂性/亲水性19SIPI-4884SIPI-4887活性化合物活性化合物R=H, CH(CH3)2,cyclopropylR=H, F. Cl, CH3OCH3,CH(CH3)2(O,S,N)HNNCH3HNOHNHNCH3NH2HNN化学合成SHNSCOOEtFSFClNClCOOEtNOHCOOEtFClDIBALHNSCH2OHFSNSCH2ClFSNSCH2P(O)Ph2FSP(OEt)Ph2COOBu-tOOCH3CH3OHCNSCOOBu-tOOCH3CH3FS n-BuLiNSOHOHFSCOOHNSOHOHFSCOOBu-tNSCOO-OHOHFS Ca2+21.

14、NaOH2. CaCl2 SIPI-4887Qun Hao, Jing Pan, Yongjia Li, Zhengyan Cai and Weicheng Zhou. Org Process Res Dev 2013, 17:921-926 体外抑制HMG CoA还原酶的IC50编号编号ICIC5050(M)(M)编号编号ICIC5050(M)(M)瑞舒伐他汀瑞舒伐他汀9.039.03SIPI-4817SIPI-481710.6710.67匹伐他汀匹伐他汀10.6710.67SIPI-4825SIPI-482511.9411.94阿托伐他汀阿托伐他汀13.2213.22SIPI-4812SI

15、PI-481212.6512.65氟伐他汀氟伐他汀21.2121.21SIPI-4808SIPI-480814.1514.15SIPI-4888SIPI-48881.241.24SIPI-4809SIPI-480915.3715.37SIPI-4886SIPI-48863.213.21SIPI-4837SIPI-483715.7515.75SIPI-4859SIPI-48593.643.64SIPI-4813SIPI-481318.5618.56SIPI-4883SIPI-48834.354.35SIPI-4887SIPI-48874.414.41SIPI-4884SIPI-48847.937

16、.93 SIPI-4885SIPI-48859.179.17 SIPI-4858SIPI-48589.249.24 SIPI-4889SIPI-48899.289.28 SIPI-4882SIPI-488210.6010.60 SIPI-4884对对HMG CoA还原酶的抑制作还原酶的抑制作用明显优于现有药物用明显优于现有药物 剂量剂量 TCTCTGTGHDL-CHDL-CLDL-CLDL-CH/LH/L正常组正常组12.4212.424.054.050.570.534.731.031.038.258.253.533.530.710.710.420.42阿托伐他汀组阿托

17、伐他汀组20206.516.511.611.61* * *0.760.760.390.394.394.390.860.862.512.511.141.14* * *61.46* *SIPI-4888SIPI-48885 511.6411.643.673.670.740.740.350.356.636.631.321.32* * *6.406.403.273.210.31* *20207.617.611.621.62* * *0.960.960.780.784.664.623.621.531.53* * *1.441.440.

18、590.59* *SIPI-4886SIPI-48865 58.658.652.482.48* *0.700.7094.814.612.062.06* *50.45* *20208.668.660.990.99* *4.474.477.067.064.744.741.571.573.663.661.451.45* * *1.371.370.250.25* * *SIPI-4859SIPI-48595 59.669.663.693.691.951.953.993.995.355.351.971.975.075.073.023.0

19、21.291.290.680.68202010.5510.555.655.650.580.580.280.285.355.351.561.566.406.404.964.961.061.060.370.37SIPI-4883SIPI-48835 58.728.723.573.570.590.545.841.691.693.993.992.952.95* *1.911.910.760.76* *20208.058.050.780.78* * *0.510.515.310.680.683.633.630.810.81* * *1.541.540.42

20、0.42* * *SIPI-4887SIPI-48875 511.1611.163.263.260.530.516.610.800.80* * *6.336.333.043.060.46* *20207.547.541.961.96* * *1.461.461.481.484.934.930.990.992.732.731.621.62* * *00.90* * *SIPI-4884SIPI-48845 93.891.501.501.021.02* *4.754.750.780.783.463.462

21、.092.09* * *1.581.580.420.42* * *20205.575.572.412.41* * *0.450.450.270.273.373.371.531.531.941.941.301.30* * *50.65* * *SIPI-4885SIPI-48855 59.759.755.535.511.114.984.981.581.514.611.561.560.790.79* *2023.721.261.260.600.60* * *4.984.980.950.954.084.0

22、82.752.75* *1.541.540.630.63* * *SIPI-4858SIPI-48585 511.6311.660.584.981.581.514.600.6020208.538.531.811.81* *0.420.484.980.950.954.084.082.752.75* *1.331.330.530.53* *SIPI-4889SIPI-48895 512.4012.407.707.700.540.526.321.381.38

23、6.516.513.533.53* *1.431.430.770.77* *20206.256.252.522.52* * *0.970.970.940.945.065.060.910.914.304.301.651.65* *20.92* * *SIPI-4882SIPI-48825 514.1314.134.294.290.560.516.211.851.856.756.755.975.970.920.920.450.4520208.888.883.273.270.350.350.070.07* * *3.773.771.041.042.522

24、.522.162.16* * *1.791.790.720.72* * *高血脂鹌鹑模型的降血脂药效学 n=8SIPI-4884在鹌鹑模型显著的降血脂作用 -58.1%-76.5%-69.6%-26.7%-55.1%-47.6%2.2 fold3.1 fold3.08 fold*:p0.01; *:p0.05豚鼠模型:SIPI-4884作用特点优于阿托伐他汀nSIPI4884 可选择性地降低低密度脂蛋白胆固醇(LDL-C)，对高密度脂蛋白胆固醇(HDL-C)没有影响n阿托伐他汀组，降低LDL-C的同时，也降低了HDL-Cn提示SIPI-4884具有优于阿托伐他汀的作用特点 -40.1%-56.

25、2%-48.7%-68.8%1.9 倍1.2 倍SIPI4887对兔动脉粥样硬化模型血清CHO的影响 分组分组剂量剂量（mg/kg）NCHO（mmol/L）造模前造模前造模造模8周周给药给药4周周给药给药6周周给药给药8周周正常正常/80.860.440.680.29*0.510.17*0.860.16*0.660.11*模型模型/100.870.3237.9715.5840.5113.3932.107.5437.2710.32阿托伐他汀阿托伐他汀380.870.3036.2111.6830.645.49*24.255.75*23.686.08*SIPI-48871.5100.940.3736

26、.0811.8937.107.1928.426.3129.668.773100.920.2736.7611.7628.807.20*22.996.41*22.798.79*6100.920.2336.9811.8424.797.48*19.435.07*19.238.55*P0.05，*P0.01，与模型组比较SIPI4887对兔动脉粥样硬化模型LDL-C的影响分组分组剂量剂量（mg/kg）NLDL-C（mmol/L）造模前造模前造模造模4周周造模造模8周周给药给药2周周给药给药4周周给药给药6周周给药给药8周周正常正常/80.320.240.360.11*0.200.14*0.240.08*

27、0.170.09*0.180.04*0.150.04*模型模型/100.340.2316.535.4630.6915.2730.4810.6133.7410.9826.708.0827.918.05阿托伐他汀阿托伐他汀380.340.1615.095.2728.679.6223.466.1525.475.37*19.725.76*18.576.50*SIPI-48871.5100.380.1813.905.6728.009.1624.757.1731.816.3223.685.8421.516.093100.360.1417.607.6928.6111.3821.957.34*23.726.9

28、6*18.275.68*17.718.21*6100.310.1517.385.0527.868.5419.596.44*22.156.52*15.044.23*15.867.56*P0.05，*P0.01，与模型组比较SIPI-4887低剂量组 SIPI-4887中剂量组 SIPI-4887高剂量组 阿托伐他汀组 正常组模型组分组分组剂量剂量mg/kgmg/kgN N主动脉粥样硬化病变百分比（）主动脉粥样硬化病变百分比（）正常正常/ /8 80.000.000.000.00* * *模型模型/ /101077.8177.8113.4613.46阿托伐他汀阿托伐他汀3 38 849.9149.

29、9125.0325.03* * *SIPI-4887SIPI-48871.51.5101050.0150.0126.8726.87* * *3 3101035.6935.6924.0324.03* * *6 6101027.6227.6217.1017.10* * *SIPI-4887对家兔主动脉粥样硬化的影响小鼠口服SIPI4887肝脏及血液药物浓度28研究结果表明：小鼠口服SIPI-4887后，肝脏中的药物浓度均比血中药物浓度高，提示药物会向肝脏聚集SIPI-4887(HSIPI-4887(H3 3) )在在SDSD大鼠体内大鼠体内ADMEADME性质：性质：u约15%的药物被吸收，大部分

30、药物未被吸收而以原形药物形式排出体外u吸收的药物主要分布在肝中u代谢途径是苯硫基被谷胱甘肽取代生成代谢产物M1，代谢产物M1在肠道内发生还原反应，裂解脱去谷胱甘肽生成M2uM1体外实验证明为活性物u上述结果支持药物肝靶向的设计上述结果支持药物肝靶向的设计药代特点和肝靶向药代性质：不经P450酶系代谷胱甘肽代谢物具有活性SIPI-4887在SD大鼠体内的代谢途径 代谢产物M1的合成及抑酶活性编号编号ICIC5050（MM）瑞舒伐他汀瑞舒伐他汀11.211.2阿托伐他汀阿托伐他汀28.628.6匹伐他汀匹伐他汀8.28.2SIPI-4887SIPI-488710.610.6SIPI-9304SIP

31、I-930412.512.5SIPI-4887及其代谢物体外抑酶活性Achievement1.Product:SIPI-4887作为1类新药开发2.Patent3.Paper已授权中国专利7份，美国专利2份1. 蔡正艳，周伟澄. 4-(氟苯基)-3-羟甲基-2-环丙基-喹啉的制备方法 授权专利号 ZL2005 1 0031049.4，授权日2008年12月24日 2. 蔡正艳，周伟澄，郝群. 喹啉类化合物及其中间体、制备方法和应用 授权专利号：ZL200610148118.4,授权日：2010年8月25日 3. 蔡正艳，周伟澄. 4-取代苯氧基喹啉类化合物及其中间体、制备方法和应用 授权号：Z

32、L200710036427.7,授权日：2010年12月8日 4. 蔡正艳，周伟澄，郝群，施振华，盛雨辰，施明玉，梁清宇. 喹啉类化合物及其药物组合物、制备方法和应用 授权专利号：ZL200810036930.7，授权日：2011年8月31日 5. 赵士魁，周伟澄，汤洁盈. 2-环丙基-4-取代苯硫基喹啉类化合物及其中间体、制备方法和应用 授权号：ZL200910055106.0，授权日：2012.8.29 6. 赵士魁，周伟澄，孟祥国，茅迪，李泳佳. 2-环丙基-4-(N-甲基取代苯胺基)喹啉类化合物及其中间体、制备方法和应用 授权号：ZL 200910055454.8,授权日：2012年6

33、月27日 7. 潘竞，蔡正艳，周伟澄，沈芳，毛黎光. 一类嘧啶类化合物及其中间体、制备方法和应用 授权号：ZL200910199486.5,授权日：2013年4月3日 8. Zhengyan Cai, Weicheng Zhou, Qun Hao, Zhenhua Shi, Yucheng Sheng, Mingyu Shi, Qingning Liang. Quinolone compounds, pharmaceutical composition, preparation methods and uses thereof 授权号：US 8227612B2 授权日：Jul. 24, 201

34、29. Zhengyan Cai, Weicheng Zhou, Qun Hao. Quinoline Compounds, Intermediates, Preparation Methods and Uses thereof 授权号：US8349867B2，授权日：Jan 8, 2013发表该课题相关SCI论文1. Zhenfa Zhang, Weicheng Zhou and Aizhen Yu. Synthesis and antibacterial activity of 7-(substituted)aminomethyl quinolones Bioorg Med Chem Le

35、tt 2004, 14:393-395 2. Zhenfa Zhang, Weicheng Zhou. Arylation of nitromethane: masked nucleophilic formylation of fluoroquinolones. Tetrahedron Lett 2005, 46:3855 3. Zhenyan Cai, Weicheng Zhou, Lixin Sun. Synthesis and HMG CoA Reductase Inhibition of 4-Thiophenyl Quinolines as Potential Hypocholeste

36、rolemic Agents Bioorg Med Chem 2007, 15:7809 4. Xiang Ma, Weicheng Zhou, Reto Brun. Synthesis, in vitro antitrypanosomal and antibacterial activity of phenoxy, phenylthio or benzyloxy substituted quinolones Bioorg Med Chem Lett 2009,19:9865. Shikui Zhao, Weicheng Zhou, Jun Liu. Synthesis and HMG-CoA

37、 reductase inhibition of 2-cyclopropyl-4-thiophenyl-quinoline mevalonolactones Bioorg Med Chem 2009, 17:7915 6. Shikui Zhao, Weicheng Zhou. A regioselective SNAr reaction of poly-halo-quinoline-3-carboxylates with phenol, thiophenol or N-methylaniline Syn Communi 2011, 41:20 7. Qun Hao, Zhengyan Cai

38、, Jing Pan, Yongjia, Li, Yuye Xia, Yang Min, Yuchen Sheng and Weicheng Zhou. Synthesis and Anti-Hypercholesterolemic Evaluations of Calcium Salts of 4-Substituted Quinoline-Based Mevalonic Acid Chem Biol Drug Des 2011, 78:7308. Qun Hao, Jing Pan, Yongjia Li, Zhengyan Cai and Weicheng Zhou. Developme

39、nt of a Practical and Efficient Synthesis of SIPI-4884, a HMG CoA Reductase Inhibitor for the Treatment of Hypercholesterolemia Org Process Res Dev 2013, 17:921-926 已发表相关论文1.郝群，蔡正艳，潘竞，李泳佳，周伟澄. (3R,5S,6E)-7-(4-对氟苯硫基喹啉-6,7,8-三氟-3-基)-3,5-二羟基庚烯酸钙有关物质的合成 中国医药工业杂志 2010，41(12):884-890 2.蔡正艳，周伟澄. 3-羟基-3-甲基戊

40、二酰辅酶A还原酶抑制剂的构效关系研究进展 中国新药杂志 2006，15(22):1907-1912 3.赵士魁，周伟澄. 降血脂药物研究进展 中国医药工业杂志 2009，40(7):536-542 4.汤洁盈，蔡正艳，周伟澄. 肝选择性他汀类药物研究进展 国际药学研究杂志 2011, 38(3):189-1945.李泳佳，张顺利，郝 群，蔡正艳，周伟澄. 降血脂候选新药SIPI-4884有关物质的HPLC测定 中国医药工业杂志 2012，43(4):281-285 6.Zhenyan Cai, Jing Pan, Quan Hao, Weicheng Zhou, Luyong Zhang Sy

41、nthesis of 4-phenoxy quinolone mevalonolactones and evaluation of their HMG CoA reductase inhibition activities J Chin Pharmaceutical Sci 2010, 19:15 谢谢大家u参与本课题获博士学位的学生1.张贞发，2.蔡正艳，3.赵士魁，4.郝群u参与本课题获硕士学位的学生1.马翔，2.潘竟，3.孙桂芳，4.李泳佳，5.汤洁盈脂蛋白分类u乳糜微粒(CM) d1.063， HDL越高，动脉粥样硬化风险越小侧链的结构改造侧链的结构改造u3,5-二羟基戊酸或内酯是药效

42、团，手性碳原子3R,5S(碳链为双键)，3R,5R (碳链为单键)u氟伐他汀为顺式异构体，(3R,5S)有药理活性，(3S,5R)无药理活性，其它药物为单一异构体u开环羧酸的活性优于内酯OHOHCOOMOOOH碳链母环碳链母环12345 RONXOHOR 1R 2R 3RONFOOH匹伐他汀匹伐他汀先导化合物先导化合物目标化合物目标化合物本课题组对他汀类的结构改造首次发现4-取代苯硫(氧、氮)基喹啉类衍生物，具有自主知识产权X=O, S, N，可保持或增强其活性，抑制酶活性：S O N实现肝选择性，通过母环的结构修饰合适的亲脂性/亲水性38SIPI-4884SIPI-4887活性化合物活性化合

43、物R=H, CH(CH3)2,cyclopropylR=H, F. Cl, CH3OCH3,CH(CH3)2(O,S,N)HNNCH3HNOHNHNCH3NH2HNNSIPI4887对兔动脉粥样硬化模型血清CHO的影响 分组分组剂量剂量（mg/kg）NCHO（mmol/L）造模前造模前造模造模8周周给药给药4周周给药给药6周周给药给药8周周正常正常/80.860.440.680.29*0.510.17*0.860.16*0.660.11*模型模型/100.870.3237.9715.5840.5113.3932.107.5437.2710.32阿托伐他汀阿托伐他汀380.870.3036.21

44、11.6830.645.49*24.255.75*23.686.08*SIPI-48871.5100.940.3736.0811.8937.107.1928.426.3129.668.773100.920.2736.7611.7628.807.20*22.996.41*22.798.79*6100.920.2336.9811.8424.797.48*19.435.07*19.238.55*P0.05，*P0.01，与模型组比较发表该课题相关SCI论文1. Zhenfa Zhang, Weicheng Zhou and Aizhen Yu. Synthesis and antibacterial activity of 7-(substituted)aminomethyl quin