CN116621801A - 一种香豆素类衍生物及其制备方法和应用 - Google Patents
一种香豆素类衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及医药领域，具体涉及一种含有式(Ⅰ)的香豆素类化合物及其在制备细菌生物膜抑制剂中的应用。本发明所涉及的香豆素类化合物经体内外药效验证，所得化合物大都具有优秀的细菌生物膜抑制活性，可用于制备抗生物膜剂，具有开发为新型抗菌药物的潜力。
Description
技术领域
本发明属于医药领域，具体涉及一种香豆素类衍生物制备方法及其在制备细菌生物膜抑制剂中的应用。
背景技术
20世纪40年代，抗生素的发现，无疑是人类对抗病原微生物的一场胜利，数以万计的生命被拯救。抗生素优异的杀菌功效和较强的选择性一度使人们认为感染性疾病将成为过去，但是，抗生素的滥用和过量使用加剧了病原微生物的变异和进化，使其耐药性不断增强，从而出现具有多重耐药性的“超级细菌”，其耐药性主要通过以下几种机制表现：(1)产生破坏抗生素的酶，如β-内酰胺类酶；(2)改变抗生素作用靶点的化学性质；(3)对细胞外排药物机制的适应；(4)通过降低细胞壁的通透性来阻止药物扩散进入细胞内；(5)细菌形成生物膜抵御药物。随着抗生素的广泛使用，我们目睹了临床上因细菌耐药性产生导致的感染治疗失败，从而对人类健康和生存构成了重大威胁的惊人现象，因此临床上迫切需要新型抗生素和抗菌策略来解决细菌耐药性这一世界性难题。
细菌耐药问题日益突出，每年约有1600万病人直接死于细菌感染。研究发现，其中超过70％的恶性感染与细菌形成生物膜耐药有关。在自然界中，大多数细菌可以附着在不同的表面并形成生物膜。生物膜是一种复杂的细菌聚集体，被细胞外聚合物(EPS)包裹在自生基质中，受温度和营养成分等影响。细菌形成生物膜后，生物膜内的细菌可以逃避宿主的免疫反应，抵御抗菌药物治疗的能力是浮游生物的1000倍。细菌形成生物膜是导致细菌耐药的重要原因之一，研发细菌生物膜抑制剂是应对细菌抗生素耐药问题的策略之一。遗憾的是，目前尚无细菌生物膜抑制剂成功应用于临床，因此研究新型生物膜抑制剂有望缓解细菌耐药问题，具有重要的科学意义。香豆素是一类苯并吡喃酮的天然产物，具有多种药理性质，包括抗抑郁、抗菌、抗炎、抗胆碱酯酶、抗血栓和抗癌等药理活性，为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种香豆素类化合物，该化合物通过抑制细菌生物膜的形成，从而克服细菌对于抗生素的耐药性，具有开发成抗生物膜药物的潜力。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此，本发明提出一种含有式(I)所示结构的香豆素类化合物及其制备方法和用途，所述化合物可选择性作用于铜绿假单胞菌，抑制铜绿假单胞菌生物膜形成。
本发明的第一方面，提供式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药：
n＝3，4，5，6
RI＝-H、6'-F、6'-Br、6'-CH3、7'-OCH3
本发明的第二方面，提供一种药物组合物，包括所述式(I)所示化合物、或其药学上可接受的盐、异构体、溶剂合物或前药中的至少一种，以及任选的药学上可接受的赋形剂或载体。
本发明所述化合物、或其药学上可接受的盐、异构体、溶剂合物或前药，或者所述药物组合物可以单位剂量形式给药，给药途径可为口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠。给药剂型可为片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、或冻干粉针剂。可以为普通制剂、缓释制剂、控释制剂及各种微粒给药系统。
通常本发明的药物组合物含有质量百分比为0.1～99.9％的所述化合物、或其药学上可接受的盐、异构体、溶剂合物或前药。
在本发明的一些实施方式中，所述药物组合物的给药形式包括将所述化合物、或其药学上可接受的盐、异构体、溶剂合物或前药与其他活性药物成分同时、分别或依次给药。
本发明还提供了一种联用药物，包括式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药中的至少一种，以及环丙沙星。
优选的，式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药与环丙沙星的质量比为50：0.5～10，优选50：1～5。
本发明的第三方面，提供上述式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药，或上述的药物组合物在制备抗生物膜剂中的应用。
优选的，所述生物膜为细菌生物膜。更优选的，所述细菌为铜绿假单胞菌。
本发明还提供上述式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药，或上述的药物组合物在制备抗菌药物中的应用。
优选的，所述菌为细菌，更优选为铜绿假单胞菌。
本发明的式(I)所示化合物，尤其是化合物7-((6-甲基香豆素-4-基)氧)-N-羟基庚酰胺，具有优秀的生物膜抑制活性。
本发明所述的式(I)所示香豆素类衍生物，具有如表1所示的化学结构：
表1化合物的结构与命名
本申请中术语：“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。
“药物组合物”包括含治疗有效量的本发明的化合物的产品，以及直接地或间接地由本申请化合物的组合产生的任何产品。
本发明的第四方面，提供式(I)所示的香豆素类衍生物的制备方法，具体包括以下步骤：
(1.1)将不同基团取代的2-羟基苯乙酮、碳酸二乙酯与NaH置于溶剂中，反应结束后的反应液经纯化得到化合物1a-1e；
(1.2)将化合物1a-1e与及K2CO3置于溶剂中，得到的反应液经纯化得到化合物2a-2q；
(1.3)将化合物2a-2q与盐酸羟胺、氢氧化钾置于溶剂中，得到的反应液经纯化得到化合物3a-3q。
此时的合成路线为：
根据本发明实施方式的化合物，至少具备如下有益效果：
(1)本发明提供了一种含有式(I)所示结构的香豆素类化合物，其中香豆素苯环6号位被甲基取代的化合物3p，具有优秀的细菌生物膜抑制活性，IC50值较低。
(2)本发明式(I)所示化合物的制备方法具有路线短、产率高、后处理方便、经济性好的优点。
附图说明
图1为化合物3p对CIP的增效作用。(A)Control组、单独CIP给药组和3p-CIP联合给药组小鼠伤口感染区域的细菌涂板结果。每组实验重复3次。(B)小鼠伤口感染区域的细菌存活率。*P<0.05，**P<0.01，***P<0.001，****P<0.0001。(C)对小鼠伤口感染区域的拍照监测。(D)小鼠伤口面积的监测，使用Image J计算伤口面积。(E)Control组、CIP组和3p-CIP组小鼠心、肝、脾、肺、肾的代表性组织免疫图像。
具体实施方式
以下结合具体实施方式对本发明作进一步说明。
实施例1：6-氟-4-羟基-香豆素(1b)的制备。
将原料5-氟-2-羟基苯乙酮(1000.00mg，6.49mmol)与NaH(778.50mg，32.44mmol)置于250ml双口瓶中，加入甲苯30ml，0℃下搅拌反应30min后，向反应瓶中加入碳酸二乙酯(1150.00mg，9.75mmol)，继续在100℃下反应4h。反应完毕后加水淬灭反应，并用稀盐酸调节PH为2，有固体析出，抽滤并水洗固体，得1b为白色固体1048.70mg，产率：89.71％。1H NMR(400MHz,DMSO)δ12.72(s,1H),7.61–7.47(m,2H),7.47–7.36(m,1H),5.63(s,1H).13C NMR(101MHz,DMSO)δ165.25,165.23,162.11,158.32(d,1JC-F＝241.1Hz),150.26(d,4JC-F＝1.5Hz),120.45(d,2JC-F＝24.6Hz),118.95(d,3JC-F＝8.6Hz),117.39(d,3JC-F＝8.6Hz),109.10(d,2JC-F＝25.0Hz).
实施例2：6-溴-4-羟基-香豆素(1c)的制备。
以5-溴-2-羟基苯乙酮(1000.00mg，4.65mmol)和碳酸二乙酯(824.00mg，6.98mmol)为原料，合成方法同化合物1b，得1c为白色固体958.20mg，产率：85.49％。1HNMR(400MHz,DMSO)δ7.88(s,1H),7.77(d,J＝8.7Hz,1H),7.34(d,J＝8.7Hz,1H),5.62(s,1H).13CNMR(101MHz,DMSO)δ165.08,161.88,153.00,135.54,125.81,119.24,118.35,116.11,92.06.
实施例3：6-甲基-4-羟基-香豆素(1d)的制备。
以5-甲基-2-羟基苯乙酮(1000.00mg，6.66mmol)和碳酸二乙酯(1180.00mg，9.99mmol)为原料，合成方法同化合物1b，得1d为白色固体1124.30mg，产率：95.82％。1HNMR(400MHz,DMSO)δ12.44(s,1H),7.59(s,1H),7.43(d,J＝7.3Hz,1H),7.24(d,J＝8.4Hz,1H),5.57(s,1H),2.36(s,3H).13C NMR(101MHz,DMSO)δ166.07,162.49,152.11,133.91,133.58,123.21,116.57,115.91,91.40,20.78.
实施例4：7-甲氧基-4-羟基-香豆素(1e)的制备。
以4-甲氧基-2-羟基苯乙酮(1000.00mg，6.02mmol)和碳酸二乙酯(1066.3mg，9.03mmol)为原料，合成方法同化合物1b，得1e为白色固体866.50mg，产率：74.56％。1HNMR(400MHz,DMSO)δ12.77(s,1H),8.13(d,J＝8.4Hz,1H),7.34(d,J＝10.3Hz,2H),5.86(s,1H),4.27(s,3H).13C NMR(101MHz,DMSO)δ166.52,163.37,162.76,155.87,124.77,112.27,109.39,100.95,88.95,56.32.
实施例5：4-((香豆素-4-基)氧)丁酸甲酯(2a)的制备。
将原料1a即4-羟基香豆素(500.00mg，3.08mmol)、K2CO3(1065.50mg，7.71mmol)置于25ml双口瓶中，加入2ml DMF做溶剂，搅拌反应30min，再向反应瓶中加入4-溴丁酸甲酯(0.44ml，3.39mmol)，于80℃下继续反应4h。反应结束后，将反应液冷却至室温，用稀盐酸调节PH为7，依次用二氯甲烷萃取反应液2次，水洗2次，有机相用无水硫酸钠干燥后抽滤，将滤液减压浓缩，并在乙酸乙酯和石油醚中重结晶，析出固体后抽滤，得2a为白色固体638.40mg，产率：79.03％。1H NMR(400MHz,CDCl3)δ7.78(dd,J＝7.9,1.5Hz,1H),7.54(td,J＝8.0,7.4,1.6Hz,1H),7.32–7.24(m,2H),5.66(s,1H),4.18(t,J＝6.1Hz,2H),3.69(s,3H),2.57(t,J＝7.2Hz,2H),2.25(p,J＝6.8Hz,2H).13C NMR(101MHz,CDCl3)δ173.02,165.41,162.78,153.30,132.42,123.88,122.93,116.76,115.60,90.61,68.21,51.82,30.33,23.89.
实施例6：5-((香豆素-4-基)氧)戊酸甲酯(2b)的制备。
以1a(500.00mg，3.08mmol)、5-溴戊酸甲酯(0.47ml，3.39mmol)为原料，合成方法同化合物2a，得2b为白色固体724.70mg，产率：85.14％。1HNMR(400MHz,CDCl3)δ7.82(dd,J＝7.9,1.3Hz,1H),7.59–7.51(m,1H),7.35–7.23(m,2H),5.67(s,1H),4.15(t,J＝6.0Hz,2H),3.70(s,3H),2.45(t,J＝7.1Hz,2H),2.03–1.93(m,2H),1.93–1.84(m,2H).13CNMR(101MHz,CDCl3)δ173.53,165.58,162.92,153.33,132.39,123.89,123.00,116.77,115.70,90.48,68.85,51.66,33.44,27.96,21.48.
实施例7：6-((香豆素-4-基)氧)己酸甲酯(2c)的制备。
以1a(500.00mg，3.08mmol)、6-溴己酸甲酯(0.55ml，3.39mmol)为原料，合成方法同化合物2a，得2c为白色固体642.90mg，产率：71.91％。1H NMR(400MHz,CDCl3)δ7.82(dd,J＝7.9,1.2Hz,1H),7.58–7.52(m,1H),7.34–7.27(m,2H),5.67(s,1H),4.14(t,J＝6.3Hz,2H),3.68(s,3H),2.38(t,J＝7.4Hz,2H),1.94(dt,J＝14.2,6.4Hz,2H),1.75(dt,J＝15.2,7.4Hz,2H),1.62–1.52(m,2H).13C NMR(101MHz,CDCl3)δ173.83,165.64,162.96,153.35,132.36,123.86,122.99,116.77,115.76,90.43,69.07,51.57,33.84,28.22,25.56,24.53.
实施例8：7-((香豆素-4-基)氧)庚酸甲酯(2d)的制备。
以1a(500.00mg，3.08mmol)、7-溴庚酸甲酯(0.58ml，3.39mmol)为原料，合成方法同化合物2a，得2d为白色固体777.00mg，产率：82.91％。1HNMR(400MHz,CDCl3)δ7.82(d,J＝7.9Hz,1H),7.55(t,J＝7.8Hz,1H),7.34–7.26(m,2H),5.66(s,1H),4.13(t,J＝6.3Hz,2H),3.67(s,3H),2.35(t,J＝7.4Hz,2H),1.92(p,J＝6.6Hz,2H),1.69(p,J＝7.4Hz,2H),1.55(dt,J＝14.9,7.3Hz,2H),1.44(q,J＝7.9Hz,2H).13C NMR(101MHz,CDCl3)δ174.04,165.68,162.99,153.34,132.34,123.86,123.00,116.76,115.79,90.39,69.24,51.52,33.89,28.73,28.31,25.68,24.74.
实施例9：4-(6-氟香豆素-4-基)氧)丁酸甲酯(2e)的制备。
以1b(300.00mg，1.67mmol)、4-溴丁酸甲酯(0.24ml，1.83mmol)为原料，合成方法同化合物2a，得2e为白色固体318.10mg，产率：67.96％。1H NMR(400MHz,CDCl3)δ7.46(dd,J＝8.3,2.6Hz,1H),7.31–7.26(m,2H),5.72(s,1H),4.21(t,J＝6.1Hz,2H),3.73(s,3H),2.59(t,J＝7.1Hz,2H),2.27(p,J＝6.6Hz,2H).13C NMR(101MHz,CDCl3)δ172.94,164.53(d,4JC-F＝2.7Hz),162.39,158.62(d,1JC-F＝243.9Hz),149.42(d,4JC-F＝6.7Hz),119.91(d,2JC-F＝24.4Hz),118.43(d,3JC-F＝8.3Hz),116.59,108.76(d,2JC-F＝25.3Hz),91.37,68.47,51.87,30.27,23.81.
实施例10：5-(6-氟香豆素-4-基)氧)戊酸甲酯(2f)的制备。
以1b(300.00mg，1.67mmol)、5-溴戊酸甲酯(0.20ml，1.83mmol)为原料，合成方法同化合物2a，得2f为白色固体350.00mg，产率：71.22％。1H NMR(400MHz,CDCl3)δ7.48(dd,J＝8.4,2.7Hz,1H),7.31–7.26(m,2H),5.71(s,1H),4.16(t,J＝6.0Hz,2H),3.71(s,3H),2.46(t,J＝7.1Hz,2H),2.03–1.93(m,2H),1.93–1.83(m,2H).13C NMR(101MHz,CDCl3)δ173.45,164.69(d,4JC-F＝2.7Hz),162.49,158.63(d,1JC-F＝243.8Hz),149.43(d,4JC-F＝2.0Hz),119.87(d,2JC-F＝24.5Hz),118.40(d,3JC-F＝8.2Hz),116.62(d,3JC-F＝9.0Hz),108.82(d,2JC-F＝25.4Hz),91.20,69.12,51.68,33.38,27.88,21.44.
实施例11：6-(6-氟香豆素-4-基)氧)己酸甲酯(2g)的制备。
以1b(300.00mg，1.67mmol)、6-溴己酸甲酯(0.29ml，1.83mmol)为原料，合成方法同化合物2a，得2g为淡黄色固体305.90mg，产率：59.41％。1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.4Hz,1H),7.29(t,J＝6.5Hz,2H),5.71(s,1H),4.15(t,J＝6.0Hz,2H),3.69(s,3H),2.40(t,J＝7.2Hz,2H),1.95(p,J＝6.6Hz,2H),1.76(p,J＝8.4,7.9Hz,2H),1.57(p,J＝7.8,7.3Hz,2H).13C NMR(101MHz,CDCl3)δ173.78,164.75(d,4JC-F＝2.3Hz),162.54,158.62(d,1JC-F＝243.5Hz),149.43(d,4JC-F＝1.8Hz),119.84(d,2JC-F＝24.2Hz),118.39(d,3JC-F＝8.3Hz),116.69(d,3JC-F＝9.0Hz),108.80(d,2JC-F＝25.3Hz),91.14,69.28,51.58,33.80,28.17,25.51,24.50.
实施例12：7-(6-氟香豆素-4-基)氧)庚酸甲酯(2h)的制备。
以1b(300.00mg，1.67mmol)、7-溴庚酸甲酯(0.31ml，1.83mmol)为原料，合成方法同化合物2a，得2h为淡黄色固体365.60mg，产率：67.92％。1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.3Hz,1H),7.28(d,J＝7.4Hz,2H),5.71(s,1H),4.14(td,J＝6.7,2.1Hz,2H),3.69(d,J＝2.5Hz,3H),2.36(td,J＝7.5,2.3Hz,2H),2.00–1.87(m,2H),1.77–1.63(m,2H),1.60–1.50(m,2H),1.49–1.40(m,2H).13C NMR(101MHz,CDCl3)δ174.01,164.79(d,4JC-F＝2.2Hz),162.58,158.62(d,1JC-F＝243.7Hz),149.44(d,4JC-F＝2.0Hz),119.82(d,2JC-F＝24.5Hz),118.39(d,3JC-F＝8.4Hz),116.68,108.81(d,2JC-F＝25.3Hz),91.11,69.49,51.53,33.87,28.71,28.26,25.65,24.71.
实施例13：4-(6-溴香豆素-4-基)氧)丁酸甲酯(2i)的制备。
以1c(300.00mg，1.24mmol)、4-溴丁酸甲酯(0.18ml，1.37mmol)为原料，合成方法同化合物2a，得2i为白色固体292.90mg，产率：69.24％。1H NMR(400MHz,CDCl3)δ7.94–7.86(m,1H),7.64(ddd,J＝8.6,4.6,2.3Hz,1H),7.21(dd,J＝8.8,4.6Hz,1H),5.70(d,J＝4.5Hz,1H),4.21(q,J＝5.9Hz,2H),3.74(d,J＝4.6Hz,3H),2.59(td,J＝7.0,4.6Hz,2H),2.28(dq,J＝11.0,6.4Hz,2H).13C NMR(101MHz,CDCl3)δ172.95,164.22,162.05,152.18,135.27,125.58,118.60,117.21,116.75,91.37,68.59,51.92,30.33,23.79.
实施例14：5-(6-溴香豆素-4-基)氧)戊酸甲酯(2j)的制备。
以1c(300.00mg，1.24mmol)、5-溴戊酸甲酯(0.19ml，1.37mmol)为原料，合成方法同化合物2a，得2j为白色固体351.70mg，产率：79.85％。1H NMR(400MHz,CDCl3)δ7.93(d,J＝2.3Hz,1H),7.64(dd,J＝8.8,2.4Hz,1H),7.21(d,J＝8.8Hz,1H),5.69(s,1H),4.16(t,J＝6.1Hz,2H),3.72(s,3H),2.46(t,J＝7.1Hz,2H),1.98(dq,J＝11.2,6.2Hz,2H),1.93–1.85(m,2H).13C NMR(101MHz,CDCl3)δ173.48,164.37,162.17,152.19,135.24,125.65,118.59,117.29,116.74,91.21,69.23,51.72,33.39,27.87,21.43.
实施例15：6-(6-溴香豆素-4-基)氧)己酸甲酯(2k)的制备。
以1c(300.00mg，1.24mmol)、6-溴己酸甲酯(0.22ml，1.37mmol)为原料，合成方法同化合物2a，得2k为白色固体326.10mg，产率：71.23％。1HNMR(400MHz,CDCl3)δ7.91(s,1H),7.64(d,J＝8.7Hz,1H),7.21(d,J＝8.6Hz,1H),5.68(s,1H),4.14(t,J＝5.7Hz,2H),3.70(s,3H),2.40(t,J＝6.9Hz,2H),2.02–1.89(m,2H),1.81–1.73(m,2H),1.64–1.51(m,2H).13CNMR(101MHz,CDCl3)δ173.80,164.42,162.19,152.19,135.19,125.64,118.58,117.34,116.70,91.15,69.41,51.62,33.80,28.17,25.49,24.49.
实施例16：7-(6-溴香豆素-4-基)氧)庚酸甲酯(2l)的制备。
以1c(300.00mg，1.24mmol)、7-溴庚酸甲酯(0.24ml，1.37mmol)为原料，合成方法同化合物2a，得2l为白色固体410.60mg，产率：86.40％。1H NMR(400MHz,CDCl3)δ7.92(d,J＝2.3Hz,1H),7.68–7.60(m,1H),7.25–7.16(m,1H),5.69(s,1H),4.14(t,J＝6.4Hz,2H),3.69(s,3H),2.36(t,J＝7.4Hz,2H),1.93(p,J＝6.7Hz,2H),1.78–1.65(m,2H),1.55(p,J＝7.2Hz,2H),1.45(p,J＝7.4,6.7Hz,2H).13C NMR(101MHz,CDCl3)δ174.04,164.47,162.24,152.20,135.18,125.66,118.58,117.38,116.71,91.12,69.61,51.55,33.89,28.72,28.26,25.65,24.72.
实施例17：4-(6-甲基香豆素-4-基)氧)丁酸甲酯(2m)的制备。
以1d(300.00mg，1.70mmol)、4-溴丁酸甲酯(0.25ml，1.87mmol)为原料，合成方法同化合物2a，得2m为白色固体312.90mg，产率：66.62％。1H NMR(400MHz,CDCl3)δ7.59–7.54(m,1H),7.36(dd,J＝8.4,1.9Hz,1H),7.21(d,J＝8.4Hz,1H),5.66(s,1H),4.19(t,J＝6.1Hz,2H),3.72(s,3H),2.60(t,J＝7.2Hz,2H),2.42(s,3H),2.27(p,J＝6.6Hz,2H).13CNMR(101MHz,CDCl3)δ173.05,165.45,163.06,151.49,133.62,133.43,122.55,116.56,115.25,90.57,68.16,51.84,30.41,23.92,20.91.
实施例18：5-(6-甲基香豆素-4-基)氧)戊酸甲酯(2n)的制备。
以1d(300.00mg，1.70mmol)、5-溴戊酸甲酯(0.27ml，1.87mmol)为原料，合成方法同化合物2a，得2n为白色固体342.10mg，产率：69.31％。1H NMR(400MHz,CDCl3)δ7.59(s,1H),7.36(d,J＝8.4Hz,1H),7.22(d,J＝8.4Hz,1H),5.65(s,1H),4.15(t,J＝5.9Hz,2H),3.71(s,3H),2.46(t,J＝7.1Hz,2H),2.43(s,3H),1.98(dt,J＝12.7,6.2Hz,2H),1.90(d,J＝7.2Hz,2H).13C NMR(101MHz,CDCl3)δ173.54,165.59,163.15,151.49,133.59,133.38,122.61,116.53,115.32,90.41,68.79,51.67,33.45,27.96,21.49,20.92.
实施例19：6-(6-甲基香豆素-4-基)氧)己酸甲酯(2o)的制备。
以1d(300.00mg，1.70mmol)、6-溴己酸甲酯(0.30ml，1.87mmol)为原料，合成方法同化合物2a，得2o为白色固体380.70mg，产率：73.58％。1H NMR(400MHz,CDCl3)δ7.62–7.55(m,1H),7.36(dd,J＝8.5,1.9Hz,1H),7.21(d,J＝8.4Hz,1H),5.65(s,1H),4.13(t,J＝6.4Hz,2H),3.69(s,3H),2.43(s,3H),2.40(t,J＝7.4Hz,2H),2.00–1.89(m,2H),1.83–
1.74(m,2H),1.63–1.53(m,2H).13C NMR(101MHz,CDCl3)δ173.84,165.66,163.21,151.51,133.59,133.36,122.61,116.54,115.39,90.37,69.02,51.58,33.85,28.24,25.56,24.55,20.92.
实施例20：7-(6-甲基香豆素-4-基)氧)庚酸甲酯(2p)的制备。
以1d(300.00mg，1.70mmol)、7-溴庚酸甲酯(0.33ml，1.87mmol)为原料，合成方法同化合物2a，得2p为白色固体416.40mg，产率：76.94％。1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.35(d,J＝8.4Hz,1H),7.21(d,J＝8.4Hz,1H),5.64(s,1H),4.12(t,J＝6.3Hz,2H),3.68(s,3H),2.42(s,3H),2.36(d,J＝7.3Hz,2H),1.93(s,2H),1.70(s,2H),1.61–1.51(m,2H),1.46(q,J＝6.4,5.5Hz,2H).13C NMR(101MHz,CDCl3)δ174.04,165.68,163.22,151.49,133.56,133.32,122.60,116.51,115.41,90.32,69.19,51.52,33.90,28.74,28.31,25.69,24.74,20.91.
实施例21：5-(7-甲氧基香豆素-4-基)氧)戊酸甲酯(2r)的制备。
以1e(300.00mg，1.55mmol)、5-溴戊酸甲酯(0.24ml，1.71mmol)为原料，合成方法同化合物2a，得2r为白色固体283.70mg，产率：59.75％。1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.8Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),6.79(d,J＝2.4Hz,1H),5.54(s,1H),4.13(t,J＝5.9Hz,2H),3.87(s,3H),3.70(s,3H),2.44(t,J＝7.1Hz,2H),2.00–1.92(m,2H),1.91–1.84(m,2H).13C NMR(101MHz,CDCl3)δ173.55,165.99,163.44,163.22,155.16,124.05,112.20,108.93,100.43,87.99,68.67,55.73,51.66,33.45,27.98,21.48.
实施例22：N-羟基-4-((香豆素-4-基)氧)丁酰胺(3a)的制备。
将盐酸羟胺(738.00mg，11.44mmol)与氢氧化钾(1283.60mg，22.88mmol)先在甲醇溶剂中反应30min后，抽滤取滤液，加入反应物2a(300.00mg，1.14mmol)，继续反应30min。反应结束后，用稀盐酸调节反应液PH为7，并向反应液中加入冰水，析出固体，若无固体析出，则将反应液减压浓缩至析出固体，将析出的固体抽滤并水洗，得3a为白色固体184.30mg，产率：61.41％。1H NMR(400MHz,DMSO)δ10.47(s,1H),8.76(s,1H),7.82(d,J＝7.7Hz,1H),7.65(t,J＝8.3Hz,1H),7.36(dd,J＝13.8,7.7Hz,2H),5.86(s,1H),4.20(t,J＝6.0Hz,2H),2.21(t,J＝7.2Hz,2H),2.06(p,J＝6.5Hz,2H).13C NMR(101MHz,DMSO)δ168.93,165.38,162.11,153.20,133.17,124.58,123.50,116.83,115.67,90.89,69.29,29.12,24.61.HRMS(ESI)ofcompound3a:calcd.forC13H13NO5[M+H]+＝264.0866,found[M+H]+＝264.0874.
实施例23：N-羟基-5-((香豆素-4-基)氧)戊酰胺(3b)的制备。
以2b(200.00mg，0.72mmol)、盐酸羟胺(467.00mg，7.24mmol)为原料，合成方法同化合物3a，得3b为白色固体115.50mg，产率：57.85％。1HNMR(400MHz,DMSO)δ10.40(s,1H),8.72(s,1H),7.80(d,J＝7.8Hz,1H),7.66(t,J＝7.8Hz,1H),7.43–7.33(m,2H),5.88(s,1H),4.22(t,J＝6.0Hz,2H),2.06(t,J＝7.1Hz,2H),1.81(dt,J＝13.2,6.0Hz,2H),1.71(p,J＝6.6,6.1Hz,2H).13C NMR(101MHz,DMSO)δ169.31,165.40,162.14,153.22,133.19,124.66,123.25,116.92,115.72,90.95,69.52,32.20,27.92,22.09.HRMS(ESI)ofcompound3b:calcd.forC14H15NO5[M+H]+＝278.1023,found[M+H]+＝278.1016.
实施例24：N-羟基-6-((香豆素-4-基)氧)己酰胺(3c)的制备。
以2c(300.00mg，1.03mmol)、盐酸羟胺(666.00mg，10.33mmol)为原料，合成方法同化合物3a，得3c为白色固体287.00mg，产率：95.65％。1H NMR(400MHz,DMSO)δ10.42(s,1H),8.69(s,1H),7.80(d,J＝7.8Hz,1H),7.66(t,J＝8.4Hz,1H),7.44–7.32(m,2H),5.88(s,1H),4.20(t,J＝6.1Hz,2H),2.00(t,J＝7.2Hz,2H),1.82(p,J＝6.2Hz,2H),1.59(p,J＝7.3Hz,2H),1.52–1.36(m,2H).13C NMR(101MHz,DMSO)δ169.44,165.43,162.15,153.23,133.19,124.67,123.28,116.92,115.73,90.94,69.86,32.61,28.15,25.50,25.24.HRMS(ESI)ofcompound3c:calcd.forC15H17NO5[M+H]+＝292.1179,found[M+H]+＝292.1178
实施例25：N-羟基-7-((香豆素-4-基)氧)庚酰胺(3d)的制备。
以2d(200.00mg，0.66mmol)、盐酸羟胺(424.00mg，6.57mmol)为原料，合成方法同化合物3a，得3d为白色固体158.90mg，产率：78.83％。1HNMR(400MHz,DMSO)δ10.27(s,1H),8.79(s,1H),7.80(d,J＝7.6Hz,1H),7.65(t,J＝7.5Hz,1H),7.48–7.20(m,2H),5.87(s,1H),4.19(s,2H),1.96(t,J＝6.8Hz,2H),1.87–1.74(m,2H),1.62–1.50(m,2H),1.50–1.40(m,2H),1.38–1.27(m,2H).13C NMR(101MHz,DMSO)δ169.51,165.44,162.14,153.22,133.17,124.67,123.27,116.90,115.73,90.91,69.90,32.66,28.70,28.31,25.60,
25.48.HRMS(ESI)ofcompound3d:calcd.forC16H19NO5[M+H]+＝306.1336,found[M+H]+＝306.1331.
实施例26：4-((6-氟香豆素-4-基)氧)-N-羟基丁酰胺(3e)的制备。
以2e(200.00mg，0.71mmol)、盐酸羟胺(460.00mg，7.14mmol)为原料，合成方法同化合物3a，得3e为白色固体169.60mg，产率：84.94％。1HNMR(400MHz,DMSO)δ10.45(s,1H),8.74(s,1H),7.62–7.49(m,2H),7.46(s,1H),5.93(s,1H),4.20(s,2H),2.20(s,2H),2.05(s,1H).13C NMR(101MHz,DMSO)δ168.95,164.54(d,4JC-F＝2.4Hz),161.87,158.47(d,1JC-F＝240.9Hz),149.52,120.51(d,2JC-F＝24.3Hz),118.97(d,3JC-F＝8.6Hz),116.75(d,3JC-F＝8.9Hz),109.19(d,2JC-F＝25.8Hz),91.62,69.58,29.19,24.56.HRMS(ESI)of compound3e:calcd.forC13H12FNO5[M+H]+＝282.0772,found[M+H]+＝282.0788.
实施例27：5-((6-氟香豆素-4-基)氧)-N-羟基戊酰胺(3f)的制备。
以2f(200.00mg，0.68mmol)、盐酸羟胺(438.00mg，6.80mmol)为原料，合成方法同化合物3a，得3f为白色固体155.40mg，产率：77.40％。1HNMR(400MHz,DMSO)δ10.40(s,1H),8.71(s,1H),7.63–7.36(m,3H),5.95(s,1H),4.21(s,2H),2.05(s,2H),1.80(s,2H),1.70(s,2H).13C NMR(101MHz,DMSO)δ169.30,164.53(d,4JC-F＝2.3Hz),161.90,158.46(d,1JC-F＝241.0Hz),149.54(d,4JC-F＝1.4Hz),120.53(d,2JC-F＝24.3Hz),119.10(d,3JC-F＝8.9Hz),116.80(d,3JC-F＝9.3Hz),108.84(d,2JC-F＝25.5Hz),91.70,69.78,32.19,27.83,22.03.HRMS(ESI)ofcompound3f:calcd.forC14H14FNO5[M+H]+＝296.0929,found[M+H]+＝296.0938.
实施例28：6-((6-氟香豆素-4-基)氧)-N-羟基己酰胺(3g)的制备。
以2g(100.00mg，0.32mmol)、盐酸羟胺(209.00mg，3.24mmol)为原料，合成方法同化合物3a，得3g为白色固体82.50mg，产率：83.36％。1H NMR(400MHz,DMSO)δ10.36(s,1H),8.68(s,1H),7.62–7.35(m,3H),5.95(s,1H),4.19(s,2H),2.00(s,2H),1.82(s,2H),1.68–1.53(m,2H),1.50–1.35(m,2H).13C NMR(101MHz,DMSO)δ169.44,164.55(d,4JC-F＝1.8Hz),161.89,158.45(d,1JC-F＝240.9Hz),149.55(d,4JC-F＝2.0Hz),120.52(d,2JC-F＝24.9Hz),119.09(d,3JC-F＝8.3Hz),116.78(d,3JC-F＝8.8Hz),108.83(d,2JC-F＝25.1Hz),91.69,70.10,32.60,28.07,25.45,25.23.HRMS(ESI)ofcompound3g:calcd.forC15H16FNO5[M+H]+
＝310.1085,found[M+H]+＝310.1089.
实施例29：7-((6-氟香豆素-4-基)氧)-N-羟基庚酰胺(3h)的制备。
以2h(100.00mg，0.31mmol)、盐酸羟胺(200.00mg，3.10mmol)为原料，合成方法同化合物3a，得3h为白色固体73.90mg，产率：73.76％。1H NMR(400MHz,DMSO)δ10.34(s,1H),8.66(s,1H),7.61–7.42(m,3H),5.94(s,1H),4.19(s,2H),1.96(t,J＝6.7Hz,2H),1.81(s,2H),1.60–1.49(m,2H),1.49–1.41(m,2H),1.40–1.27(m,2H).13C NMR(101MHz,DMSO)δ169.52,164.57(d,4JC-F＝2.0Hz),161.89,158.45(d,1JC-F＝241.2Hz),149.53,120.51(d,2JC-F＝24.4Hz),119.09(d,3JC-F＝8.5Hz),116.79(d,3JC-F＝9.0Hz),108.83(d,2JC-F＝25.3Hz),91.66,70.15,32.66,28.69,28.24,25.51,25.46.HRMS(ESI)of compound 3h:calcd.forC16H18FNO5[M+H]+＝324.1242,found[M+H]+＝324.1247.
实施例30：4-((6-溴香豆素-4-基)氧)-N-羟基丁酰胺(3i)的制备。
以2i(200.00mg，0.59mmol)、盐酸羟胺(378.00mg，5.86mmol)为原料，合成方法同化合物3a，得3i为白色固体188.90mg，产率：93.59％。1H NMR(400MHz,DMSO)δ10.51(s,1H),8.74(s,1H),7.91(d,J＝2.2Hz,1H),7.81(d,J＝11.2Hz,1H),7.37(d,J＝8.8Hz,1H),5.94(s,1H),4.21(t,J＝6.0Hz,2H),2.20(t,J＝7.2Hz,2H),2.05(p,J＝6.2Hz,2H).13C NMR(101MHz,DMSO)δ168.90,164.20,161.59,152.27,135.72,125.61,119.28,117.56,116.51,91.74,69.67,29.14,24.55.HRMS(ESI)of compound 3i:calcd.forC13H12BrNO5[M+H]+＝341.9972,found[M+H]+＝341.9965.
实施例31：5-((6-溴香豆素-4-基)氧)-N-羟基戊酰胺(3j)的制备。
以2j(200.00mg，0.56mmol)、盐酸羟胺(363.00mg，5.63mmol)为原料，合成方法同化合物3a，得3j为白色固体167.60mg，产率：84.03％。1HNMR(400MHz,DMSO)δ10.43(s,1H),8.71(s,1H),7.87–7.76(m,2H),7.37(d,J＝8.6Hz,1H),5.94(s,1H),4.21(s,2H),2.06(t,J＝6.7Hz,2H),1.88–1.76(m,2H),1.75–1.64(m,2H).13C NMR(101MHz,DMSO)δ169.30,164.15,161.60,152.27,135.68,125.31,119.36,117.59,116.45,91.79,69.87,32.18,27.85,22.06.HRMS(ESI)ofcompound3j:calcd.forC14H14BrNO5[M+H]+＝356.0128,found[M+H]+＝356.0129.
实施例32：6-((6-溴香豆素-4-基)氧)-N-羟基己酰胺(3k)的制备。
以2k(200.00mg，0.54mmol)、盐酸羟胺(349.00mg，5.42mmol)为原料，合成方法同化合物3a，得3k为白色固体174.50mg，产率：87.30％。1HNMR(400MHz,DMSO)δ10.37(s,1H),8.68(s,1H),7.89–7.75(m,2H),7.37(d,J＝8.7Hz,1H),5.94(s,1H),4.19(t,J＝6.2Hz,2H),2.00(t,J＝7.2Hz,2H),1.83(p,J＝6.4Hz,2H),1.59(p,J＝7.3Hz,2H),1.43(p,J＝7.9Hz,2H).13C NMR(101MHz,DMSO)δ169.45,164.17,161.61,152.27,135.67,125.31,119.36,117.59,116.44,91.79,70.20,32.61,28.09,25.44,25.24.HRMS(ESI)ofcompound3k:calcd.forC15H16BrNO5[M+H]+＝370.0285,found[M+H]+＝370.0272.
实施例33：7-((6-溴香豆素-4-基)氧)-N-羟基庚酰胺(3l)的制备。
以2l(200.00mg，0.52mmol)、盐酸羟胺(337.00mg，5.22mmol)为原料，合成方法同化合物3a，得3l为白色固体193.10mg，产率：96.65％。1H NMR(400MHz,DMSO)δ10.40(s,1H),8.78(s,1H),7.94–7.74(m,2H),7.38(d,J＝8.8Hz,1H),5.94(s,1H),4.20(t,J＝6.3Hz,23H),1.97(t,J＝7.3Hz,2H),1.82(p,J＝6.4Hz,2H),1.53(p,J＝7.4Hz,2H),1.44(dt,J＝14.6,7.6Hz,2H),1.33(dt,J＝13.4,7.0Hz,2H).13C NMR(101MHz,DMSO)δ169.48,164.20,161.62,152.28,135.68,125.33,119.38,117.61,116.45,91.77,70.27,32.69,28.69,28.22,25.53,25.49.HRMS(ESI)ofcompound3l:calcd.forC16H18BrNO5[M+H]+＝384.0441,found[M+
H]+＝384.0455.
实施例34：4-((6-甲基香豆素-4-基)氧)-N-羟基丁酰胺(3m)的制备。
以2m(200.00mg，0.72mmol)、盐酸羟胺(467.00mg，7.20mmol)为原料，合成方法同化合物3a，得3m为白色固体112.50mg，产率：56.35％。1HNMR(400MHz,DMSO)δ10.43(s,1H),8.83(s,1H),7.60(s,1H),7.45(dd,J＝8.4,1.6Hz,1H),7.27(d,J＝8.4Hz,1H),5.83(s,1H),4.19(t,J＝6.0Hz,2H),2.38(s,3H),2.21(t,J＝7.2Hz,2H),2.05(p,J＝6.5Hz,2H).13CNMR(101MHz,DMSO)δ168.90,165.40,162.26,151.37,133.99,133.93,123.02,116.63,115.35,90.81,69.28,29.15,24.59,20.83.HRMS(ESI)ofcompound3m:calcd.
forC14H15NO5[M+H]+＝278.1023,found[M+H]+＝278.1017.
实施例35：5-((6-甲基香豆素-4-基)氧)-N-羟基戊酰胺(3n)的制备。
以2n(200.00mg，0.69mmol)、盐酸羟胺(444.00mg，6.90mmol)为原料，合成方法同化合物3a，得3n为白色固体157.40mg，产率：78.31％。1H NMR(400MHz,DMSO)δ10.42(s,1H),8.73(s,1H),7.56(s,1H),7.45(d,J＝7.9Hz,1H),7.27(d,J＝8.2Hz,1H),5.84(s,1H),4.20(t,J＝6.1Hz,2H),2.37(s,3H),2.10–2.03(m,2H),1.84–1.77(m,2H),1.74–1.66(m,2H).13CNMR(101MHz,DMSO)δ169.29,165.39,162.28,151.38,133.99,133.93,122.73,116.71,115.39,90.87,69.48,32.18,27.91,22.05,20.85.HRMS(ESI)ofcompound3n:calcd.forC15H17NO5[M+H]+＝292.1179,found[M+H]+＝292.1176.
实施例36：6-(6-甲基香豆素-4-基)氧)-N-羟基己酰胺(3o)的制备。
以2o(200.00mg，0.66mmol)、盐酸羟胺(424.00mg，6.57mmol)为原料，合成方法同化合物3a，得3o为白色固体158.60mg，产率：78.70％。1H NMR(400MHz,DMSO)δ10.31(s,1H),8.78(s,1H),7.56(s,1H),7.45(dd,J＝8.5,1.8Hz,1H),7.27(d,J＝8.4Hz,1H),5.84(s,1H),4.18(t,J＝6.3Hz,2H),2.38(s,3H),2.00(t,J＝7.3Hz,2H),1.82(p,J＝6.5Hz,2H),1.60(p,J＝7.3Hz,2H),1.44(p,J＝7.4,6.8Hz,2H).13C NMR(101MHz,DMSO)δ169.42,165.42,162.28,151.38,133.98,133.96,122.75,116.71,115.39,90.86,69.82,32.60,28.15,25.47,25.25,20.85.HRMS(ESI)ofcompound3o:calcd.forC16H19NO5[M+H]+＝306.1336,found[M+H]+＝306.1341.
实施例37：7-((6-甲基香豆素-4-基)氧)-N-羟基庚酰胺(3p)的制备。
以2p(200.00mg，0.63mmol)、盐酸羟胺(405.00mg，6.28mmol)为原料，合成方法同化合物3a，得3p为白色固体181.30mg，产率：90.11％。1H NMR(400MHz,DMSO)δ10.35(s,1H),8.68(s,1H),7.55(s,1H),7.45(d,J＝8.4Hz,1H),7.27(d,J＝8.4Hz,1H),5.83(s,1H),4.18(t,J＝6.3Hz,2H),2.37(s,3H),1.97(d,J＝14.6Hz,2H),1.81(p,J＝6.5Hz,2H),1.54(p,J＝7.5Hz,2H),1.44(q,J＝7.2Hz,2H),1.33(p,J＝7.0,6.2Hz,2H).13C NMR(101MHz,DMSO)δ169.56,165.43,162.28,151.38,133.98,133.95,122.73,116.70,115.39,90.82,69.86,32.67,28.70,28.31,25.56,25.47,20.85.HRMS(ESI)ofcompound3p:calcd.forC17H21NO5[M+H]+
＝320.1492,found[M+H]+＝320.1490.
实施例38：4-((7-甲氧基香豆素-4-基)氧)-N-羟基丁酰胺(3q)的制备。
以2q(200.00mg，0.68mmol)、盐酸羟胺(440.00mg，6.82mmol)为原料，合成方法同化合物3a，得3q为白色固体107.50mg，产率：53.90％。1H NMR(400MHz,DMSO)δ10.45(s,1H),8.74(s,1H),7.71(d,J＝8.5Hz,1H),7.02–6.87(m,2H),5.70(s,1H),4.18(s,2H),3.85(s,3H),2.19(t,J＝6.2Hz,2H),2.10–1.97(m,2H).13C NMR(101MHz,DMSO)δ168.91,165.82,163.36,162.53,155.09,124.62,112.58,108.79,100.91,88.29,69.12,56.37,29.10,24.63.HRMS(ESI)ofcompound3q:calcd.forC14H15NO6[M+H]+＝294.0972,found[M+H]+＝294.0965.
实施例39：结晶紫染色法测定衍生物对铜绿假单胞菌PAO1的生物膜抑制率。
实验方法：在LB琼脂平板上挑落单克隆细菌在LB培养基中过夜培养，取100μL的菌液测定OD600，用LB培养基把细菌稀释至OD600＝0.01；用含细菌的培养基把化合物配制至工作浓度，取200μL加入至96孔板中，同时设定阳性药阿奇霉素(Azithromycin)组、空白组(Control组，只有细菌)、阴性对照组(Blank组，只有培养基)，96孔板的四周用200μL的LB培养基封边，防止挥发导致的边缘效应，每组数据设置4～6个复孔，将96孔板放置于37℃培养箱静止培养16h；小心吸出菌液，用200μL的PBS溶液清洗3次；加入200μL的0.1％结晶紫溶液染色30min；小心吸出结晶紫，然后用200μL的PBS溶液清洗3次；晾干后加入200μL30％的冰醋酸溶液溶解结晶紫，并放置于微量摇床上震荡摇匀5min后测OD550；计算生物膜抑制率＝[(ControlOD值-BlankOD值)-(给药组组OD值-BlankOD值)]/(ControlOD值-BlankOD值)×100％。结晶紫染色法测定的香豆素衍生物的IC50结果见表2：
表2香豆素类衍生物对铜绿假单胞菌PAO1生物膜的抑制率
a，对于所有化合物，其IC50均在阳性药阿奇霉素的生物膜抑制率>30％下测得。
实验结果：根据表2的实验结果可得出，溴的引入可使化合物活性得到略微提升，而氟为最优吸电子取代基团。除了碳链长度为4的化合物3f，它在吸电子取代基化合物中拥有最好的生物膜抑制活性，IC50仅为9.80±9.91μM，氟的引入使化合物生物膜抑制活性随着碳链延长而提升。随后，我们也探究了给电子取代基对于化合物活性的影响，结果表明6号位甲基取代的化合物3m-3p的生物膜抑制活性大幅度提高，且抑制效果随着碳链延长显著提升，这与之前氟取代得到的结果基本一致。在所有化合物中，6号位甲基取代且碳链长度为6个碳的化合物3p具有最优生物膜抑制活性，其IC50＝3.66±2.74μM，有作为先导化合物进一步研究的潜力。以上实验结果表明该系列衍生物具有优秀的生物膜抑制活性。
实施例40：化合物3p在小鼠伤口感染模型中对环丙沙星(CIP)的增效研究
实验方法：本动物实验按照国家有关动物实验的规定进行。铜绿假单胞菌PAO1菌株用于本动物实验，雌性5周龄Babl/c小鼠购自SPF(Beijing)Biotechnology.co.Ltd.整个实验过程中小鼠生活环境保持恒温25℃，12h的光/夜循环，提供充足的食物和水。首先将20只小鼠随机分为4组，5只/组。用4％水合氯醛进行麻醉处理后，将小鼠背部毛发剃掉，在每只小鼠背部建立4-5mm的圆形伤口，并在创面接种5×108CFU的PAO1，建立伤口感染模型24h。然后分别对不同组小鼠给以不同药物进行治疗(生理盐水，1mg/ml CIP，0.005mg/mlCIP+50μM3p，0.001mg/ml CIP+50μM3p)。连续给药3天后，取小鼠伤口处皮肤做CFU计数，同时每天对小鼠伤口拍照监测，以计算伤口面积。
实验结果：如图1所示，小鼠连续给药3天后，联合给药治疗组小鼠伤口处的细菌明显比生理盐水组(Control)治疗的细菌减少很多。通过对伤口处细菌存活率的计算，生理盐水组细菌存活率计为100％，用1mg/ml CIP治疗3天后，细菌基本全部清除，存活率为0％。0.005mg/ml CIP+50μM3p联合用药治疗后，存活的细菌极少，存活率趋近于0％，说明3p对CIP的增效效果达到了200倍。0.001mg/ml CIP+50μM3p联合用药组，细菌存活率相对Control组来说也相对较低，仅为5％左右。随后，对小鼠伤口面积的监测也得到了一致的实验结果。3p与稀释后的CIP联合给药3天后，伤口面积与单独CIP给药组基本相同，且都比Control组的伤口面积小很多，在第9天，伤口愈合程度达到80％左右。此外，根据小鼠器官组织学H&E染色结果来看，化合物3p对小鼠心、肝、脾、肺、肾均未造成损害。以上结果均表明，3p作为生物膜抑制剂，对CIP具有较好的增效效果，其增效效果为200-1000倍。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于所述技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (9)
1.式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药：
2.根据权利要求1所述的式(1)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药，其特征在于具有如下所示的化学结构：
3.一种药物组合物，其特征在于，包括权利要求1所述的式(I)所示化合物、或其药学上可接受的盐、异构体、溶剂合物或前药中的至少一种，以及任选的药学上可接受的赋形剂或载体。
4.一种联用药物，包括式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药中的至少一种，以及环丙沙星。
5.根据权利要求4所述的联用药物，其中式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药与环丙沙星的质量比为50：0.5～10，优选50：1～5。
6.权利要求1所述的式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药在制备抗生物膜剂中的应用。
7.权利要求1所述的式(I)所示化合物或其药学上可接受的盐、异构体、溶剂合物或前药在制备抗菌药物中的应用。
8.根据权利要求7所述的应用，所述菌为细菌，优选为铜绿假单胞菌。
9.权利要求1中所述的式(I)所示的香豆素类衍生物的制备方法，包括以下步骤：
(1.1)将不同基团取代的2-羟基苯乙酮、碳酸二乙酯与NaH置于溶剂中，反应结束后的反应液经纯化得到化合物1a-1e；
(1.2)将化合物1a-1e与及K2CO3置于溶剂中，得到的反应液经纯化得到化合物2a-2q；
(1.3)将化合物2a-2q与盐酸羟胺、氢氧化钾置于溶剂中，得到的反应液经纯化得到化合物3a-3q；
此时的合成路线为：
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