CN105622492A - 具有抗耐药菌活性的查尔酮衍生物 - Google Patents

具有抗耐药菌活性的查尔酮衍生物 Download PDF

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CN105622492A
CN105622492A CN201610022180.2A CN201610022180A CN105622492A CN 105622492 A CN105622492 A CN 105622492A CN 201610022180 A CN201610022180 A CN 201610022180A CN 105622492 A CN105622492 A CN 105622492A
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CN105622492B (zh
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张恩
秦上尚
徐帅民
王铭铭
赵娣
白鹏燕
周萌萌
王平
王上
王亚娜
崔得运
化永刚
刘宏民
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Zhengzhou University
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明属于药物化学领域，公开了具有抗耐药菌活性的新型查尔酮衍生物及其合成方法。本发明通过两步反应，简单、快速得到目标产物，化合物结构如下：？

Description

具有抗耐药菌活性的查尔酮衍生物
技术领域
本发明属于药物化学技术领域，公开了具有抗耐药菌活性的新型查尔酮衍生物的及其合成方法。
背景技术
20世纪40年代，当青霉素广泛应用于临床治疗严重葡萄球菌感染时，抗菌药物耐药随之成为临床工作者面临的一个严重挑战。1947年，从第1例对青霉素耐药的金黄色葡萄球菌病例被报道及至1952年，临床病例分离出的金黄色葡萄球菌株，其中的75％表现对青霉素耐药。近几年，随着对碳青霉烯类抗菌药物耐药的肠杆菌科细菌的出现，预示着抗菌药物已进入后抗菌素时代。同时，高收入国家的医院、社区和农业生产中抗菌药物的使用越来越多，耐药菌株层出不穷，迫使临床医生只能选择价格昂贵的新一代抗菌药物或广谱抗菌药物；而在中、低收入国家，随人们收入以及患者住院率和院内感染率的增加，抗菌药物的使用量也在不断增长。不断增长的抗生素用量以及在抗生素应用过程中出现的不合理使用造成了耐药菌数量和比例的不断增加，严重威胁临床抗感染治疗。
耐甲氧西林的金黄色葡萄球菌(Methicillin-resistantStaphylococcusaureus，MRSA)是造成医院(hospital-acquired，HA)和社区获得性(community-acquired，CA)感染的重要病原菌，能够引起多种致死性感染，如坏死性肺炎、骨髓炎、脑膜炎和心内膜炎等。近年来，MRSA在世界范围内普遍流行且危害日益严重。据统计，美国每年因MRSA感染导致死亡的患者数相当于AIDS、结核病和病毒性肝炎的总和。在我国，医院获得性MRSA(HA-MRSA)是MRSA菌株的主要来源，呈现检出率高、多重耐药(对三类或以上抗生素耐药)严重的特点。2010年度卫生部全国细菌耐药监测网的报告显示：在全国不同地区ICU来源的葡萄球菌属细菌中，MRSA的检出率达到近80％(79.6％)且超过60％的MRSA对六类或六类以上临床常用抗生素耐药。因此现有抗生素对于MRSA的治疗形势严峻。亟待开发针对MRSA有较强抑杀活性的新型抗生素。
根据文献报道，查耳酮具有抗菌活性，其结构里的α，β-不饱和羰基与细菌内的亲核基团，如蛋白质中的巯基进行共轭加成而致使细菌死亡。Naganinietal.成功合成出了一系列具有抗菌活性的查尔酮衍生物，这类查尔酮对大肠杆菌具有很好的抑制或杀灭作用，并且经抗菌实验证明，羟基在查尔酮B环的邻位取代较对位取代活性强。Liarasetal合成了一系列结构较新的查尔酮衍生物，这些查尔酮衍生物包含两个很有名的生物活性结构分子，分别是噻唑和查尔酮。这些查尔酮衍生物的抗菌和抗真菌活性引起作者的关注，数据显示这些化合物的抗菌活性几乎全部比对照组药性强。这也表明该类衍生物很可能成为新的抗菌药物替代品。
因此本研究设计与合成了一系列新型的查尔酮衍生物，体外活性实验显示该系列化合物中的几种对MRSA具有较好的抑菌活性，值得进行深入开发。
发明内容
本发明的目的在于提供一类抗耐药菌活性好的新型查尔酮衍生物。
为实现本发明，本发明合成查尔酮衍生物路线如下：
合成目标化合物如下：
1、5a：R1＝p-NH2，R2＝H，R4＝Cl，n＝1
2、5b：R1＝p-NH2，R2＝3-F，R4＝Cl，n＝1
3、5c：R1＝p-NH2，R2＝5-Br，R4＝Cl，n＝1
4、5d：R1＝p-NH2，R2＝6-Br，R4＝Cl，n＝1
5、5e：R1＝p-NH2，R2＝H，R4＝H，n＝1
6、5f：R1＝p-NH2，R2＝H，R4＝Br，n＝1
7、5g：R1＝p-NH2，R2＝H，R4＝Cl，n＝2
8、5h：R1＝p-NH2，R2＝H，R4＝Cl，n＝3
9、5i：R1＝p-NH2，R2＝H，R4＝Cl，n＝4
10、5j：R1＝o-NH2，R2＝H，R4＝Cl，n＝1
11、5k：R1＝m-NH2，R2＝H，R4＝Cl，n＝1。
采用上述路线，化合物2为2-吡啶甲醛或取代的2-吡啶甲醛合成化合物5a-5k：
12、5l：R1＝p-NH2，R2＝H，R4＝Cl，n＝1。
采用上述路线，化合物2为3-吡啶甲醛合成化合物5l：
13、5m：R1＝p-NH2，R2＝H，R4＝Cl，n＝1，
采用上述路线，化合物2为4-吡啶甲醛合成化合物5m。
具体通过如下步骤实现：
1、化合物1与化合物2发生经典的Claisen-Schmidt反应，反应条件是在氢氧化钠的催化作用下，以乙醇为溶剂，常温下进行反应得到化合物3。
2、化合物3与化合物4在弱碱K2CO3和无水丙酮中，常温下进行反应得到一系列目标化合物5a～5m。
本发明所述新型的查尔酮衍生物对革兰氏阳性菌金黄色葡萄球菌株(29213)有较好的抑菌作用，化合物5a，5f，5k，5m对多株临床耐药菌株MRSA表现出良好的抑菌效果，并且优于阳性对照药左氧氟沙星和红霉素，因此，本发明提供的此类新型查尔酮衍生物有望作为新的抗菌候选药物进行深入的研究，并对解决目前全球面临耐药菌日益严重的问题有重要意义。
具体实施方式
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器：NMR谱使用瑞典BrukerDPX-400型超导核磁共振仪测定，TMS为内标；高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测定。
实施例1
化合物5a的制备
取氢氧化钠(370mg，9.25mmol)于250ml单口圆底烧瓶中，加入50ml水室温磁力搅拌下溶解；然后将化合物1(对氨基苯乙酮)(1.00g，7.40mmol)和化合物2(2-吡啶甲醛)(722ul，7.58mmol)加入100ml锥形瓶内，加入50ml乙醇超声至该体系基本澄清，然后将该澄清溶液恒压滴加(1d/s)到上述已经搅拌氢氧化钠溶液的单口瓶内，滴加完毕后室温下继续反应，此时体系棕黄色澄清。约6h后，TLC检测(PE：EA＝1:1)显示反应完全。停止反应，将反应体系倒入约50ml冰水中，立即析出大量黄色固体，抽滤，滤饼水洗至中性，真空干燥，得到亮黄色固体化合物3(1.48g)，收率为89.2％。
取上述化合物3(100mg，0.446mmol)和碳酸钾(74mg，0.535mmol)于5ml单口圆底烧瓶，然后加入1.35ml丙酮，塞上翻口橡胶塞室温下搅拌；然后用1ml注射器通过橡胶塞向反应体系注入化合物4(氯乙酰氯)(40.3μl，0.535mmol)，体系立即由原来的橙色浑浊变为黄色浑浊。约0.5h后，TLC(PE：EA＝1:1)检测，显示反应完全，3ml冰水淬灭反应，搅拌10min后，将体系抽滤，滤饼冰水洗至中性，真空干燥得到化合物5a(119mg)。
产物为浅棕色固体，收率为89％。m.p.:137-138℃。
1HNMR(400MHz,CDCl3)δ8.70(d,J＝3.9Hz,1H),8.51(s,1H),8.18–8.08(m,3H),7.82–7.68(m,4H),7.48(d,J＝7.7Hz,1H),7.31(ddd,J＝7.6,4.8,0.9Hz,1H),4.23(s,2H).
13CNMR(101MHz,CDCl3)δ188.87,164.08,153.12,150.14,142.67,141.02,136.99,134.35,130.23,125.53,125.24,124.50,119.38,77.36,77.04,76.72,42.90.
HR-MS(ESI)CalcdforC16H14ClN2O2[M+H]+:301.0744,found:301.0744.
实施例2
化合物5b的制备
化合物1为对氨基苯乙酮，化合物2为3-氟-2-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为淡黄色固体，收率为98.8％，m.p.:157-158℃。
1HNMR(400MHz,CDCl3)δ8.43(d,J＝4.4Hz,1H),8.39(s,1H),8.10(dd,J＝24.8,12.0Hz,3H),7.98(dd,J＝15.3,1.1Hz,1H),7.66(d,J＝8.7Hz,2H),7.48–7.33(m,1H),7.28(dt,J＝8.5,4.3Hz,1H),4.16(s,2H).
13CNMR(101MHz,CDCl3)δ187.55,163.02,144.75,144.70,140.02,133.67,133.28,129.25,125.45,125.41,124.95,124.90,123.00,122.81,118.36,76.33,76.21,76.01,75.69,41.87,-0.00,-1.03.
HR-MS(ESI)CalcdforC16H13ClFN2O2[M+H]+:319.0650,found:319.0648.
实施例3
化合物5c的制备
化合物1为对氨基苯乙酮，化合物2为5-溴-2-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为淡黄色固体，收率为85.3％，m.p.:226-227℃。
1HNMR(400MHz,DMSO)δ10.72(s,1H),8.81(d,J＝1.9Hz,1H),8.23–8.08(m,4H),7.91(d,J＝8.4Hz,1H),7.80(d,J＝8.6Hz,2H),7.69(d,J＝15.4Hz,1H),4.32(d,J＝6.3Hz,2H).
13CNMR(101MHz,DMSO)δ187.63,165.24,151.71,150.73,143.11,141.26,139.75,132.41,130.02,126.29,125.69,121.21,118.86,43.60,40.13,39.92,39.71,39.51,39.30,39.09,38.88.
HR-MS(ESI)CalcdforC16H13BrClN2O2[M+H]+:378.9849,found:378.9850.
实施例4
化合物5d的制备
化合物1为对氨基苯乙酮，化合物2为6-溴-2-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为淡黄色固体，收率为73.3％，m.p.:225-226℃。
1HNMR(400MHz,DMSO)δ10.74(s,1H),8.11(dd,J＝17.6,12.0Hz,3H),7.96(d,J＝7.5Hz,1H),7.90–7.79(m,3H),7.72–7.59(m,2H),6.65(d,J＝8.6Hz,1H),4.33(d,J＝7.1Hz,2H).
13CNMR(101MHz,DMSO)δ187.58,165.25,154.26,143.17,141.65,140.60,140.43,132.31,130.06,128.94,126.30,124.30,118.88,43.60,40.13,39.92,39.71,39.50,39.30,39.09,38.88.
HR-MS(ESI)CalcdforC16H13BrClN2O2[M+H]+:378.9849,found:378.9850.
实施例5
化合物1为对氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为乙酰氯，制备方法同实施例1。
产物为淡黄色固体，收率为94.6％，m.p.:183-184℃。
1HNMR(400MHz,CDCl3)δ8.69(s,1H),8.10(t,J＝11.2Hz,3H),7.98(s,1H),7.73(dd,J＝33.0,11.1Hz,4H),7.48(d,J＝7.3Hz,1H),7.30(d,J＝6.0Hz,1H),2.22(s,3H),1.89(s,2H).
13CNMR(101MHz,CDCl3)δ189.02,168.74,153.22,150.14,142.54,142.49,136.99,133.40,130.24,125.45,125.40,124.46,118.98,77.36,77.24,77.04,76.72,24.77,0.00.
HR-MS(ESI)CalcdforC16H15N2O2[M+H]+:267.1134,found:267.1132.HR-MS(ESI)CalcdforC16H15N2O2[M+H]+:267.1134,found:267.1132.
实施例6
化合物1为对氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为溴乙酰溴，制备方法同实施例1。
产物为黄色固体，收率为84％，m.p.:185-186℃。
1HNMR(400MHz,DMSO)δ10.80(s,1H),8.70(d,J＝3.6Hz,1H),8.16(t,J＝11.4Hz,3H),8.04–7.67(m,6H),7.45(d,J＝4.1Hz,1H),4.11(s,2H).
13CNMR(101MHz,DMSO)δ187.79,165.42,152.77,149.93,143.14,142.49,137.26,132.53,129.98,125.06,124.92,124.78,118.78,40.13,39.92,39.71,39.50,39.29,39.08,38.88,30.29.
HR-MS(ESI)CalcdforC16H14BrN2O2[M+H]+:345.0239,found:345.0239.
实施例7
化合物1为对氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为氯丙酰氯，制备方法同实施例1。
产物为黄色固体，收率为98.3％，m.p.:74-75℃。
1HNMR(400MHz,CDCl3)δ8.62(d,J＝3.9Hz,1H),8.15(s,1H),8.02(dd,J＝11.9,10.7Hz,3H),7.74–7.59(m,4H),7.41(d,J＝7.7Hz,1H),7.28–7.21(m,1H),3.81(t,J＝6.4Hz,2H),2.81(t,J＝6.4Hz,2H),1.87(s,2H).
13CNMR(101MHz,CDCl3)δ188.06,167.23,152.11,149.08,141.54,141.13,136.05,132.61,129.23,124.51,124.36,123.51,118.24,76.34,76.02,75.70,39.47,38.62,-0.00,-1.02.
HR-MS(ESI)CalcdforC17H16ClN2O2[M+H]+:315.0900,found:315.0898.
实施例8
化合物1为对氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为氯丁酰氯，制备方法同实施例1。
产物为黄色固体，收率为88.7％，m.p.:155-156℃。
1HNMR(400MHz,CDCl3)δ8.69(d,J＝4.1Hz,1H),8.11(t,J＝12.4Hz,3H),7.99(s,1H),7.82–7.66(m,4H),7.48(d,J＝7.7Hz,1H),7.31(dd,J＝7.1,5.1Hz,1H),3.66(t,J＝6.1Hz,2H),2.62(t,J＝7.0Hz,2H),2.25–2.15(m,2H).
13CNMR(101MHz,CDCl3)δ188.99,170.44,153.15,150.10,142.48,142.40,137.04,133.44,130.27,125.50,125.40,124.49,119.04,77.36,77.25,77.04,76.72,44.37,34.19,27.70.
HR-MS(ESI)CalcdforC18H18ClN2O2[M+H]+:329.1057,found:329.1056.
实施例9
化合物1为对氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为氯戊酰氯，制备方法同实施例1。
产物为黄色固体，收率为92.5％，m.p.:67-68℃。
1HNMR(400MHz,CDCl3)δ8.68(d,J＝4.0Hz,1H),8.17–7.91(m,4H),7.82–7.62(m,4H),7.47(d,J＝7.7Hz,1H),7.30(dd,J＝7.0,5.1Hz,1H),3.56(d,J＝5.3Hz,2H),2.44(t,J＝6.6Hz,2H),1.86(s,6H).
13CNMR(101MHz,CDCl3)δ188.00,170.13,152.14,149.10,141.48,136.01,132.33,129.24,124.46,124.36,123.48,118.01,76.34,76.23,76.03,75.71,43.54,35.66,30.81,21.60,-0.00,-1.02.
HR-MS(ESI)CalcdforC19H20ClN2O2[M+H]+:343.1213,found:343.1216.
实施例10
化合物1为邻氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为黄色固体，收率为99.2％，m.p.:157-158℃。
1HNMR(400MHz,CDCl3)δ12.43(s,1H),8.72(dd,J＝12.7,6.3Hz,2H),8.18(dd,J＝20.0,11.3Hz,2H),7.84–7.73(m,2H),7.62(t,J＝7.9Hz,1H),7.48(d,J＝7.7Hz,1H),7.33(dd,J＝7.2,4.9Hz,1H),7.29–7.21(m,2H),4.23(s,2H).
13CNMR(101MHz,CDCl3)δ193.32,165.66,152.76,150.24,143.62,140.01,137.05,134.92,131.24,126.29,125.85,124.73,123.87,123.52,121.09,77.35,77.24,77.03,76.71,43.30,0.00.
HR-MS(ESI)CalcdforC16H14ClN2O2[M+H]+:301.0744,found:301.0746.
实施例11
化合物1为间氨基苯乙酮，化合物2为2-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为黄色固体，收率为65.8％，m.p.:117-118℃。
1HNMR(400MHz,CDCl3)δ8.69(d,J＝4.0Hz,1H),8.51(s,1H),8.12–8.05(m,2H),8.02(d,J＝8.1Hz,1H),7.90(d,J＝7.8Hz,1H),7.83–7.73(m,2H),7.54–7.48(m,2H),7.32(dd,J＝7.1,5.0Hz,1H),4.23(s,2H).
13CNMR(101MHz,CDCl3)δ189.78,164.21,153.01,150.19,143.25,138.64,137.32,137.01,129.64,125.58,125.42,125.27,124.73,124.61,120.04,77.36,77.25,77.04,76.73,42.88,-0.00.
HR-MS(ESI)CalcdforC16H14ClN2O2[M+H]+:301.0744,found:301.0747.
实施例12
化合物1为对氨基苯乙酮，化合物2为3-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为黄色固体，收率为95.4％，m.p.:242-243℃。
1HNMR(400MHz,DMSO)δ10.71(s,1H),9.03(d,J＝1.3Hz,1H),8.62(d,J＝3.8Hz,1H),8.36(d,J＝8.0Hz,1H),8.21(d,J＝8.7Hz,2H),8.10(d,J＝15.7Hz,1H),7.78(dd,J＝14.9,12.3Hz,3H),7.51(dd,J＝7.9,4.8Hz,1H),4.34(s,2H).
13CNMR(101MHz,DMSO)δ187.32,165.24,150.91,150.30,143.01,140.05,135.06,132.52,130.56,130.08,123.89,123.77,118.74,43.61,40.12,39.91,39.70,39.49,39.29,39.08,38.87.
HR-MS(ESI)CalcdforC16H14ClN2O2[M+H]+:301.0744,found:301.0742.
实施例13
化合物1为对氨基苯乙酮，化合物2为4-吡啶甲醛，化合物4为氯乙酰氯，制备方法同实施例1。
产物为黄色固体，收率为97.7％，m.p.:224-225℃。
1HNMR(400MHz,DMSO)δ10.75(s,1H),8.66(dd,J＝14.1,5.6Hz,2H),8.28–8.11(m,3H),7.83(dd,J＝14.1,7.0Hz,4H),7.68(d,J＝15.7Hz,1H),4.34(s,2H).
13CNMR(101MHz,DMSO)δ187.45,165.28,150.31,143.19,141.87,140.54,132.30,130.20,126.26,122.47,118.76,43.60,40.12,39.91,39.70,39.49,39.28,39.08,38.87.
HR-MS(ESI)CalcdforC16H14ClN2O2[M+H]+:301.0744,found:301.0743.
应用例
体外抗菌活性测试：
1、实验材料
受试菌株：分离于临床标本的11株无重复MRSA菌株。苯唑西林耐药表型阳性(≥4mg/L)，且mecA基因检测阳性。
2、实验方法
采用美国临床与实验室标准协会(CLSI,ClinicalandLaboratoryStandardsInstitute)推荐的微量肉汤稀释法进行药敏试验，操作规范参照CLSIM07-A9标准，判定标准参照CLSIM100-S24标准，具体方法如下：
(1)抗菌药物贮存液制备：制备抗菌药物贮备液的浓度为2560μg/ml，溶解度低的抗菌药物可稍低于上述浓度。所需抗菌药物溶液量或粉剂量可公式进行计算。配制好的抗菌药物贮存液应贮存于-20℃以下环境，保存期不超过6个月。
(2)待测菌的制备：用接种环挑取过夜培养的MH(A)培养皿上的单菌落于MH(B)培养基中，校准为0.5麦氏比浊标准，约含菌数1×108CFU/ml，然后稀释100倍，即得到约含菌数1×106CFU/ml的菌液，备用。
(3)分别将抗菌药物贮备液母液(2560μg/ml)稀释10倍，得到浓度为256μg/ml的抗菌药物溶液。取无菌的96孔板，第一孔加入200μL的抗菌药物，第二至十孔分别加入100μL的MH肉汤培养基，从第一孔吸取100μL加入第二孔，混匀，再吸取100μL至第三孔，依次类推，第十孔吸取100μL弃去。此时各孔药物浓度依次为：256、128、64、32、16、8、4、2、1、0.5μg/ml，第十一孔加入200μL菌液(阳性对照)，第十二孔加入200μLMH(B)培养基(阴性对照)。
(4)然后在1至10孔各加入50μL之前备好的菌液，使每管最终菌液浓度约为5×105CFU/ml，第1孔至第11孔药物浓度分别为128、64、32、16、8、4、2、1、0.5、0.25μg/ml。将接种好的96孔板放置37℃培养箱进行培养，24h观察菌液生长情况。同时用标准株做质控。
(5)结果判断与解释：在读取和报告所测试菌株的MIC前，应检查生长对照管的细菌生长情况是否良好，同时还应检查接种物的传代培养情况以确定其是否污染，质控菌株的MIC值是否处于质控范围。以肉眼观察，药物最低浓度管无细菌生长者，即为受试菌的MIC。
3、实验结果
表一：化合物5a，5e，5f，5k，5m对临床分离的多药耐药MRSA菌株(编号1-11)的MIC(μg/ml)结果
a：耐甲氧西林的金黄色葡萄球菌
由上表可见，化合物5a、5f和5m相比临床在用的治疗革兰氏阳性菌引起感染的抗菌药物而言具有明显的抗菌优势，MIC90均为16μg/ml，远小于左氧氟沙星和红霉素的＞64μg/ml，具有较好的成药前景。

Claims (3)

1.具有抗耐药菌活性的查尔酮衍生物，其特征在于，该化合物结构式如下，选以下化合物之一：
（1）5a：R2=H，R4=Cl，n=1
（2）5b：R2=3-F，R4=Cl，n=1
（3）5c：R2=5-Br，R4=Cl，n=1
（4）5d：，R2=6-Br，R4=Cl，n=1
（5）5e：R2=H，R4=H，n=1
（6）5f：R2=H，R4=Br，n=1
（7）5g：R2=H，R4=Cl，n=2
（8）5h：，R2=H，R4=Cl，n=3
（9）5i：R2=H，R4=Cl，n=4
（10）5j：R2=H，R4=Cl，n=1
（11）5k：R2=H，R4=Cl，n=1。
2.具有抗耐药菌活性的查尔酮衍生物，其特征在于，该化合物结构式如下，选以下化合物：
5l：R2=H，R4=Cl，n=1。
3.具有抗耐药菌活性的查尔酮衍生物，其特征在于，该化合物结构式如下，选以下化合物：
5m：R2=H，R4=Cl，n=1。
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