CN112159354A - 对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和应用 - Google Patents

对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和应用 Download PDF

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CN112159354A
CN112159354A CN202011025639.7A CN202011025639A CN112159354A CN 112159354 A CN112159354 A CN 112159354A CN 202011025639 A CN202011025639 A CN 202011025639A CN 112159354 A CN112159354 A CN 112159354A
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aminosalicylic acid
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杨大成
潘建芳
范莉
任艳会
唐雪梅
胡军华
徐兴然
谢建平
周围
许峻旗
吴玉珠
李洋
王颢霖
韩双
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Abstract

本发明公开了对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和应用，属于药物合成技术领域。对氨基水杨酸的氟喹诺酮类衍生物的结构式如下。体外抗菌活性测定结果表明，目标化合物对细菌的抑制活性整体很好；绝大多数化合物对毕赤酵母菌的抑菌活性整体很好，有的化合物活性甚至强于阳性对照药物；2个中间体对耻垢分枝杆菌的抑制活性强于多数阳性对照药物；部分目标化合物对柑橘病菌具有抑制活性。本发明的对氨基水杨酸的氟喹诺酮类衍生物及中间体在抗细菌、抗真菌、抗结核和抗柑橘病菌领域具有潜在的应用前景。

Description

对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和 应用
技术领域
本发明涉及药物合成技术领域，具体涉及对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和应用。
背景技术
对氨基水杨酸(简称PAS)，为一种用于治疗结核病的抗菌药。其也被用于治疗炎症性肠病，通过抑制NF-κB及清除自由基而发挥作用。主要用于治疗结核病。
PAS氨基衍生物可分为三大类。第一类是PAS席夫碱衍生物。研究结果表明，所合成的目标化合物，对耻垢分枝杆菌和牛型分枝杆菌的抑菌浓度均低于PAS；吡嗪酰胺(PZA)和PAS的席夫碱衍生物，对H37Rv抑制活性强于PZA(MIC分别为3.13和6μg/mL)。第二类是PAS腙类衍生物，将异烟肼(INH)与PAS反应制备了含有腙基的化合物，实验结果显示，均比阳性对照(MICINH＝1μg/mL、MIC环丙沙星＝1.5μg/mL和MIC诺氟沙星＝10μg/mL)好。第三类，在氨基上接一些其他官能团的衍生物，这些分子也显示很好的生物活性。
氟喹诺酮(FQs)药物是1970-1990年代开发的第三代喹诺酮类药物，具有很好的早期杀菌活性。FQs抗菌药物的构效关系研究已很深入，目前认为：喹诺酮母核的3位羧基与4为羰基不可或缺，一般不能改变；6位引入氟原子可增强抗菌作用并对金黄色葡萄球菌有抗菌活性；7位引进哌嗪环(如诺氟沙星)可提高对金黄色葡萄球菌及绿脓杆菌的抗菌作用，哌嗪环被甲基哌嗪环取代(如培氟沙星)则脂溶性增加、肠道吸收增强、细胞的穿透性提高、半衰期延长。N-l位以环丙基团(环丙沙星、克林沙星)或嗯嗪基团(氧氟沙星)修饰可扩大抗菌谱，增强对衣原体、支原体及分支杆菌(结核杆菌与麻风杆菌等)的抗菌活性，嗯嗪环还可提高水溶性，使药物在体内不被代谢，以原型经尿排泄。FQs的作用机制与其它抗生素不同，故与其它抗生素之间无交叉耐药性。
目前对FQs类药物改构主要从两方面进行：①改变氟喹诺酮的母体结构，设计新的框架结构；②对氟喹诺酮母体结构进行修饰。研究表明，C-7位取代基的性质可以极大地影响DNA促旋酶和细胞通透性，并最终影响改构分子的溶解度、生物活性、抗菌谱和药代动力学性质。迄今为止，已经通过将各种类型的取代基，包括含氮五元和六元单杂环(吡咯、六氢吡啶和哌嗪)、含氮并杂环等引入到FQs的C-7位，获得了药学、药代性能优良的抗菌型FQs，从中发现了大量结构新颖的抗菌、抗结核药物或候选药物。
真菌是细菌的一种，能引起动植物和人的各种疾病。不同真菌可以通过不同方式致病，通常分为以下几种：(1)致病性真菌感染：由外源性真菌引起，如皮肤癣病菌；(2)条件致病性真菌感染：由内源性真菌引起，如白色念珠菌等；(3)真菌超敏反应性疾病：吸入或食入菌丝或孢子引起荨麻疹、哮喘等；(4)真菌性中毒症：食用含真菌毒素的霉变粮食所致；(5)真菌毒素：与肿瘤发生有关。常用于治疗真菌病的抗真菌剂，已知唑类抗真菌剂(卢立康唑、联苯苄唑、酮康唑、咪康唑、伊曲康唑、克霉唑、奈替康唑、奥昔康唑、噻康唑、氯康唑、奥莫康唑、硫康唑及其盐等)、苄胺类抗真菌剂(布替奈芬及其盐等)、烯丙胺类抗真菌剂(特比萘酚及其盐等)、吗啉类抗真菌剂(阿莫罗芬及其盐等)、硫代氨基甲酸类抗真菌剂(利拉萘酯、托萘酯、托西拉酯等)，及抗生素类(制霉菌素、曲古霉素、拟青霉素、干蠕孢菌素、硝吡咯菌素、两性霉素等)等，但这些抗菌药物的蓄积毒性较强，常常引起肝肾损伤、消化道刺激、头晕、过敏等，所以寻找作用机理独特的新型抗菌药物成为当今药物研发的热点之一。
柑橘溃疡病分布广泛，可危害几十种芸香科植物，是影响世界柑橘生产的重大检疫性病害。其危害对柑橘叶、枝以及果实，形成典型的溃疡斑症状，如不及时治疗，病害扩散极快，将严重危害柑橘生产及影响经济效益。柑橘病菌系分化复杂、发病率高、传播快、寄主范围广，所以如何防治柑橘溃疡病一直是一个世界性难题，目前尚无一种方法可以根治。生产上常用波尔多液等含有金属铜离子的混合液体进行抑菌，需多次大量喷雾使用，既可能加速耐药性的产生，还会对土壤、其他益生菌造成毒害，因此开发新型抗柑橘病菌药物迫在眉睫。
发明内容
有鉴于此，本发明的目的在于提供对氨基水杨酸的氟喹诺酮类衍生物及其中间体、制备方法和应用。
经研究，本发明提供以下技术方案：
1、式Ⅰ所示的对氨基水杨酸的氟喹诺酮类衍生物，其消旋体、立体异构体、互变异构体、氮氧化合物或药学上可接受的盐：
Figure BDA0002702044860000021
式Ⅰ中，X选自：乙基、4-FC6H4或
Figure BDA0002702044860000022
Z选自：C、N或CR1，R1为H、烷氧基或卤素；Y选自：
Figure BDA0002702044860000023
R2和R3独立地选自为H或C1-C3烷基，m为1或2；L选自：-CO(CH2)nCO-，n为2，3或4；R选自：C1-C6烷基。
优选的，所述式Ⅰ中，Z选自：C、N或CR1，R1为H、C1-C3烷氧基、F或Cl；Y选自：
Figure BDA0002702044860000031
R2和R3独立地选自为H或甲基，m为1或2；L选自：-CO(CH2)nCO-，n为2，3或4；R选自：C1-C3烷基。
优选的，所述式Ⅰ中，Z选自：C、N或CR1，R1为H、甲氧基、F或Cl；L选自：-CO(CH2)2CO-；R选自：甲基或乙基。
优选的，式Ⅰ所示的对氨基水杨酸的氟喹诺酮类衍生物为以下化合物中的任一种：
Figure BDA0002702044860000032
Figure BDA0002702044860000041
2、上述对氨基水杨酸的氟喹诺酮类衍生物的制备方法，包括以下步骤：将对氨基水杨酸羧基进行酯化，制得中间体IM1；
Figure BDA0002702044860000042
将氟喹诺酮与linker试剂反应，制得中间体IM3；
Figure BDA0002702044860000043
将中间体IM1与中间体IM3偶联，制得对氨基水杨酸的氟喹诺酮类衍生物；
Figure BDA0002702044860000051
式中，X，Z，Y，L和R的定义均与上述的对氨基水杨酸的氟喹诺酮类衍生物结构式
中X，Z，Y，L和R的定义相同。
优选的，所述对氨基水杨酸的氟喹诺酮类衍生物的制备方法，包括以下步骤：
A、将对氨基水杨酸在酸作用下与醇反应，制得中间体IM1；所述醇为甲醇或乙醇；所述酸为硫酸；
B、将氟喹诺酮与linker试剂在有机溶剂中、碱作用下进行氨基酰化，制得中间体IM3；所述有机溶剂为二氯甲烷、氯仿、丙酮、乙酸乙酯、四氢呋喃或乙醚；所述碱为碳酸钾、碳酸钠、三乙胺或碳酸氢钠；
C、将中间体IM1与中间体IM3在有机溶剂、碱及偶联剂作用下偶联，制得对氨基水杨酸的氟喹诺酮类衍生物；所述有机溶剂为二氯甲烷、氯仿、乙腈、四氢呋喃或N,N-二甲基甲酰胺；所述碱为碳酸氢钠、三乙胺、氢氧化钠、甲醇钠或碳酸钾；所述偶联剂为二环己基碳二亚胺(DCC)、1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)或O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)。
更优选的，所述步骤B中，有机溶剂为二氯甲烷；碱为碳酸氢钠。
更优选的，所述步骤C中，有机溶剂为二氯甲烷；碱为三乙胺；偶联剂为HATU或HBTU。
3、上述制备方法制得的中间体IM1，即
Figure BDA0002702044860000052
4、上述制备方法制得的中间体IM1，即
Figure BDA0002702044860000053
在抗结核药物中的应用。
5、上述对氨基水杨酸的氟喹诺酮类衍生物在抗细菌药物中的应用。
优选的，所述对氨基水杨酸的氟喹诺酮类衍生物在抗金黄色葡萄球菌药物中的应用。
6、上述对氨基水杨酸的氟喹诺酮类衍生物在抗真菌药物中的应用。
优选的，所述对氨基水杨酸的氟喹诺酮类衍生物在抗毕赤酵母菌药物中的应用。
除另有说明外，本发明中的术语“消旋体”是指由等量对映体构成的光学不活性的有机物。“立体异构体”是指原子组成及键接相同而原子在三维空间排列上不同的分子。“氮氧化物”是指三级氮连接氧原子形成+N-O-结构单元的有机物。“药学上可接受的盐”可以是酸性盐，也可以是碱性盐，例如无机酸盐、有机酸盐、无机碱盐或有机碱盐。
术语“C1-C3烷基”指具有1-3个碳原子的直链或支链饱和一价烃基，例如甲基、乙基、丙基和异丙基。
术语“卤素”指F、Cl、Br和I。
本发明的有益效果在于：
1)本发明提供的对氨基水杨酸的氟喹诺酮类衍生物，以对氨基水杨酸为母核，对其氨基和羧基进行合理修饰，构建了一类结构新颖的对氨基水杨酸的氟喹诺酮类衍生物，产物的化学结构经1H NMR，13C NMR和HR MS确认；
2)体外抗细菌活性测定结果表明，PAS对六种细菌无抑制作用，但目标化合物的抑菌活性整体较好。对金黄色葡萄球菌，有8个化合物的MIC≤6.4μg/mL，其中TM3-3和TM6-4的MIC值分别为0.2μg/mL和0.4μg/mL，活性与阳性对照药物氟喹诺酮相当甚至更强；对于大肠杆菌，化合物TM3-7的MIC值为6.4μg/mL；对于藤黄微球菌，TM6-1与TM3-3的MIC值分别为1.6μg/mL及6.4μg/mL，强于大多数氟喹诺酮药物。这些结果表明，对氨基水杨酸的氟喹诺酮类衍生物在抗细菌领域具有潜在的应用前景；
3)体外抗真菌活性测定结果表明，所测试的16个目标分子对毕赤酵母菌的抑制活性都强于母体PAS、PAS的甲酯(IM1-1)及其乙酯(IM1-2)，整体活性很好；16个目标分子中，有10个分子的MIC值在4～128μg/mL之间，其中8个分子的MIC≤4μg/mL，与阳性对照药物氟康唑的MIC值相同。这8个目标分子对毕赤酵母菌株的抑制活性强于或相当于氟康唑，从而证明对氨基水杨酸的氟喹诺酮类衍生物在抗真菌领域具有潜在的应用前景；
4)化合物对耻垢分枝杆菌的抑制活性测定结果表明，中间体IM1-1和IM1-2的MIC值均为0.19μg/mL，强于异烟肼、利福平和多数氟喹诺酮阳性药物，证明对氨基水杨酸的氟喹诺酮类衍生物的中间体在抗结核领域具有潜在的应用前景；
5)化合物对柑橘病菌的抑制活性测试结果表明，母体PAS的其抑制活性很弱，但在1.6μg/mL测试浓度下，目标分子TM6有2个分子的抑制活性强于母体PAS；在0.64μg-/mL测试浓度下，抑制率高于40％的分子有1个。证明了对氨基水杨酸的氟喹诺酮类衍生物在抗柑橘病菌领域具有进一步研究的潜力。
具体实施方式
下面结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整的描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
一、主要试剂和仪器
对氨基水杨酸、氯乙酰氯、二氯甲烷、N,N-二甲基甲酰胺、加替沙星、克林沙星、环丙沙星、巴洛沙星、沙拉沙星、依诺沙星(>95％)；诺氟沙星、洛美沙星(AR)；浓硫酸、甲醇、碳酸氢钠、碳酸钾、无水乙醇、丁二酸酐、HBTU(AR)，其余试剂均为市售化学纯或分析纯产品。
核磁共振仪(AV-600,600MHz,TMS为内标)；高分辨质谱仪(Varian 7.0T)；熔点测定仪(X-6)；自动旋光仪(WZZ-2S)；紫外分析仪(ZF-1)；旋转蒸发仪(RE-2000)。
二、对氨基水杨酸的氟喹诺酮类衍生物的制备
1、中间体IM1-1的合成
Figure BDA0002702044860000071
向反应瓶中加入PAS 1.53g(10mmol)、甲醇25mL，室温搅拌。冰浴，滴加浓硫酸1.3mL(25mmol)，滴毕，油浴回流反应，薄层层析法(TLC)监测直至反应结束。冰浴冷却，碳酸钠溶液调节pH在7-8，冷藏，抽滤，滤饼用冰水洗涤。滤液用二氯甲烷(DCM)萃取(3×30mL)，收集有机相，饱和NaCl溶液洗涤。无水硫酸钠干燥，旋蒸，并与滤饼合并，柱层析，真空干燥，得中间体IM1-1(白色固体)1.096g，收率为65％。
2、中间体IM3-1的合成
Figure BDA0002702044860000072
向反应瓶中依次加入FQs 5mmol、DCM 20mL、丁二酸酐6mmol，室温磁力搅拌。加入研细的Na2CO3 6mmol，继续磁力搅拌，TLC检测反应进程，反应完毕后，旋蒸除溶剂。加入20mLH2O搅拌均匀，2N HCl溶液调节pH值在2-3，置于冰箱冷藏，抽滤，收集滤饼，TLC验纯，真空干燥，得中间体IM3-1，实验条件及结果如表1所示。
表1 中间体IM3-1的合成结果
Figure BDA0002702044860000081
3、对氨基水杨酸的氟喹诺酮类衍生物TM3的合成
Figure BDA0002702044860000082
向反应瓶中依次加入IM3-1、HBTU 1.1mmol、Et3N、IM1-1、DCM 3mL，45℃恒温磁力搅拌反应，TLC检测反应进程。反应完毕后，加入100mL DCM搅拌溶解，抽滤，滤液依次用饱和NaHCO3溶液(20mL×2)、1N HCl溶液(20mL×2)、饱和NaCl溶液(20mL×1)洗涤，无水硫酸钠干燥，旋蒸。柱层析(DCM/CH3OH＝200:1-50:1,v/v)和薄层层析纯化，真空干燥，得目标化合物TM3。实验条件及结果如表2所示。
表2 制备TM3的实验条件及结果
Figure BDA0002702044860000083
Figure BDA0002702044860000091
4、TM3产物结构表征数据如下：
Figure BDA0002702044860000092
TM3-1:8-Chloro-1-cyclopropyl-6-fluoro-7-(3-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanamido)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.269.1～272.3℃；1H NMR(600MHz,DMSO-d6)δ14.54(s,1H,H-15),10.62(s,1H,H-3),10.28(s,1H,H-5),8.85(s,1H,H-16),7.99(s,1H,H-9),7.97(s,1H,H-14),7.71(s,1H,H-2),7.40(s,1H,H-4),7.09(d,J＝8.7Hz,1H,H-6),4.43～4.40(m,1H,H-17),3.87(s,3H,H-1),3.68(s,4H,H-10 and H-11 and H-13),2.89(s,1H,H-13),2.71(d,J＝6.3Hz,2H,H-7),2.63(t,J＝6.3Hz,2H,H-8),1.91(s,1H,H-12),1.23(s,1H,H-12),1.21～1.18(m,2H,H-18 and H-19),1.03～0.99(m,2H,H-18 and H-19).13C NMR(151MHz,DMSO-d6)δ176.32,173.26,169.59,168.94,165.20,164.38,146.85,145.79,144.24,138.48,134.05,130.04,125.19,123.62,114.09,109.27,108.27,106.36,104.23,57.17,50.45,48.56,45.29,34.27,33.91,31.36,32.19,11.38,11.25.HR MS calcd forC29H28ClFN4O8,[M+H]+ 615.1652,found 615.1658.
TM3-2:1-Cyclopropyl-6-fluoro-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.259.3～262.9℃；1H NMR(600MHz,DMSO-d6)δ10.62(s,1H,H-3),10.41(s,1H,H-5),8.74(s,1H,H-16),7.73～7.65(m,2H,H-2 and H-14),7.58(s,1H,H-13),7.42(s,1H,H-4),7.11(d,J＝8.7Hz,1H,H-6),4.16～4.11(m,1H,H-17),3.86(s,3H,H-1),3.71(d,J＝30.8Hz,4H,H-9 and H-11),3.28(d,J＝9.3Hz,4H,H-10 and H-12),2.71(t,J＝12.1Hz,2H,H-8),2.65(d,J＝5.7Hz,2H,H-7),1.39～1.30(m,2H,H-18 and H-19),0.90～0.84(m,2H,H-18 and H-19).13C NMR(151MHz,DMSO-d6)δ171.98,170.39,169.56,167.44,161.74,146.37,132.20,132.04,131.09,129.12,111.46,110.81,107.47,106.34,72.74,67.91,63.29,60.72,52.63,38.58,32.05,30.28,28.83,27.83,23.74,22.84,14.33,11.26,8.05.HR MS calcd for C29H29FN4O8,[M+H]+ 581.2042,found 581.2050.
Figure BDA0002702044860000101
TM3-3:1-Cyclopropyl-6-fluoro-7-(3-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-N-methyl-4-oxobutanamido)piperidin-1-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.235.1～237.3℃；1H NMR(600MHz,DMSO-d6)δ14.97(s,1H,H-17),10.61(s,1H,H-3),10.26(d,J＝12.9Hz,1H,H-5),8.69(d,J＝6.0Hz,1H,H-18),7.74(t,J＝11.4Hz,1H,H-2),7.69(d,J＝8.7Hz,1H,H-15),7.37(d,J＝8.9Hz,1H,H-4),7.06(d,J＝8.3Hz,1H,H-6),4.18～4.12(m,1H,H-19),3.86(s,3H,H-1),3.79(d,J＝31.2Hz,3H,H-16),3.49～3.37(m,2H,H-10 and H-11),3.34(s,3H,H-9),3.26～3.05(m,3H,H-11 and H-14),2.96(s,2H,H-7),2.80(s,2H,H-8),1.88～1.69(m,4H,H-12 and H-13),1.12～0.96(m,4H,H-20 and H-21).13C NMR(151MHz,DMSO-d6)δ176.81,172.05,171.64,171.41,169.56,166.11,161.77,156.93,155.29,150.98,146.31,139.77,134.54,131.13,121.36,110.72,107.41,107.04,106.25,63.21,55.36,54.31,53.70,52.63,50.73,41.23,32.14,30.44,27.96,25.80,9.51,9.21.HR MS calcd for C32H35FN4O9,[M+H]+ 639.2461,found639.2456.
TM3-4:1-Cyclopropyl-6-fluoro-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanoyl)-3-methylpiperazin-1-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.164.6～166.9℃；1H NMR(600MHz,DMSO-d6)δ10.42(s,2H,H-3and H-5),8.69(s,1H,H-16),7.70(d,J＝8.1Hz,1H,H-2),7.40(s,1H,H-4),7.07(d,J＝39.3Hz,1H,H-6),4.12～3.99(m,1H,H-17),3.86(s,3H,H-1),3.68(s,3H,H-20),3.50～3.36(m,3H,H-9 and H-13),3.15(d,J＝112.3Hz,4H,H-11 and H-12),2.77(s,2H,H-7),2.63(s,2H,H-8),1.44～1.30(m,2H,H-18 and H-19),1.23(s,3H,H-10),0.97～0.68(m,2H,H-18 and H-19).13C NMR(151MHz,DMSO-d6)δ172.02,170.44,169.99,169.50(2C),161.82,146.34,131.12(2C),129.79,127.81,122.48,121.83,118.26,112.93,112.30,110.73,107.56,106.40,72.74,63.97,63.31,60.73,52.58,38.71,32.13,29.92,23.23,15.55,9.43(2C).HR MS calcd for C31H33FN4O9,[M+H]+ 647.2124,found 647.2115.
Figure BDA0002702044860000102
TM3-5:1-Ethyl-6-fluoro-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid
White solid；m.p.262.4～265.1℃；1H NMR(600MHz,DMSO-d6)δ14.96(s,1H,H-15),10.61(s,1H,H-3),10.28(s,1H,H-5),8.70(s,1H,H-16),8.36(s,1H,H-14),7.91(s,1H,H-13),7.71(d,J＝8.7Hz,1H,H-2),7.39(d,J＝1.6Hz,1H,H-4),7.09(dd,J＝8.7Hz,J＝1.8Hz,1H,H-6),4.59(q,J＝6.9Hz,2H,H-17),3.86(s,3H,H-1),3.69(d,J＝25.4Hz,4H,H-9and H-11),3.14(s,2H,H-10and H-12),3.05(s,2H,H-10 and H-12),2.72(t,J＝6.3Hz,2H,H-8),2.63(t,J＝6.3Hz,2H,H-7),1.32(t,J＝6.5Hz,3H,H-18).13C NMR(151MHz,DMSO-d6)δ177.38,171.94,170.44,169.56,166.15,161.76,148.53,147.62,146.29,137.71,135.52,131.15,125.18,120.83,116.10,110.75,107.84,107.48,106.29,52.63,51.61,51.41,45.31,41.76,36.39,32.09,27.87,7.99(s).HR MS calcd for C28H29FN4O8,[M+H]+569.2042,found 569.2034.
TM3-6:1-Ethyl-6,8-difluoro-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutan-oyl)-3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.278.5～281.4℃；1H NMR(600MHz,DMSO-d6)δ14.89(s,1H,H-15),10.61(s,1H,H-3),10.28(s,1H,H-5),8.94(s,1H,H-16),7.88(d,J＝11.6Hz,1H,H-14),7.71(d,J＝8.7Hz,1H,H-2),7.39(s,1H,H-4),7.08(d,J＝8.6Hz,1H,H-6),4.59(q,J＝3.5Hz,2H,H-17),3.86(s,3H,H-1),3.46(dd,J＝25.1,11.3Hz,2H,H-11),3.33(s,4H,H-12and H-13),3.16～2.99(m,1H,H-9),2.77(s,2H,H-7),2.62(d,J＝8.5Hz,2H,H-8),1.45(t,J＝6.9Hz,3H,H-18),1.30(dd,J＝98.4,5.2Hz,3H,H-10).13C NMR(151MHz,DMSO-d6)δ176.00,171.96,170.43,169.56,165.96,161.77,151.64(2C),146.29(2C),134.40,131.13,127.72,121.40,110.73,107.57,107.45,107.39,106.27,55.36,54.25,54.15,52.63,50.98,44.98,32.08,28.14,16.37,15.28.HR MS calcd for C29H30F2N4O8,[M+H]+601.2104,found 601.2097.
Figure BDA0002702044860000111
TM3-7:6-Fluoro-1-(4-fluorophenyl)-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.216.7～218.5℃；1H NMR(600MHz,DMSO-d6)δ15.12(s,1H,H-14),10.61(s,1H,H-3),10.26(s,1H,H-5),8.65(s,1H,H-13),7.99(d,J＝8.0Hz,1H,H-15),7.82～7.77(m,2H,H-17 and H-19),7.72(s,1H,H-2),7.44～7.40(m,2H,H-18 and H-20),7.38(d,J＝1.4Hz,1H,H-4),7.06(dd,J＝8.7Hz,J＝1.2Hz,1H,H-6),6.41(d,J＝7.1Hz,1H,H-16),3.86(s,3H,H-1),3.63(s,2H,H-9 and H-11),3.57(s,2H,H-9 and H-11),3.09(s,2H,H-10 and H-12),3.04(s,2H,H-10 and H-12),2.65(t,J＝6.2Hz,2H,H-7),2.58(t,J＝6.1Hz,2H,H-8).13C NMR(151MHz,DMSO-d6)δ177.19,171.91,170.30,169.56,166.18,161.76,154.15,152.50,149.20,146.27,139.65,136.65,131.15(2C),130.35(2C),128.30,119.19,117.84,117.69,110.74,107.93,107.49,107.07,106.29,52.64(2C),49.50(2C),44.64,31.97,27.68.HR MS calcd for C32H28F2N4O8,[M+H]+ 635.1948,found635.1949.
TM3-8:1-Ethyl-6-fluoro-7-(4-(4-((3-hydroxy-4-(methoxycarbonyl)phenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
White solid；m.p.254.3～257.7℃；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H,H-14),10.65(s,1H,H-3),10.59(s,1H,H-5),8.91(s,1H,H-15),8.04(d,J＝13.4Hz,1H,H-13),7.74(d,J＝8.6Hz,1H,H-2),7.38(s,1H,H-4),7.08(d,J＝8.5Hz,1H,H-6),4.51～4.45(q,2H,H-16),3.88(s,3H,H-1),3.68(d,J＝36.5Hz,4H,H-10 and H-12),3.30(s,4H,H-9and H-11),2.70(d,J＝5.2Hz,2H,H-8),2.64(d,J＝5.8Hz,2H,H-7),1.41(t,J＝7.0Hz,3H,H-17).13C NMR(151MHz,DMSO-d6)δ175.08,171.91,170.56,169.56,163.21,161.83,147.58,146.28,145.41,144.69,131.14,127.54,124.83,119.53,110.75,107.48,106.30,52.66(2C),47.35(2C),44.61,41.24,32.00,27.82,15.22.HR MS calcd for C27H28FN5O8,[M+H]+ 570.1995,found 570.2003.
5、TM3合成路线的选择
Figure BDA0002702044860000121
对于TM3的合成还设计了另一条路线，如式Ⅱ所示。但实验发现，中间体IM1-1和丁二酸酐反应生成中间体IM3*，实验很顺利，收率很好；然后将IM3*与FQs进行偶联反应，选择了DCC、EDCI和HBTU几种偶联剂进行偶联，在实验过程中发现，FQs基本没变化，但中间体IM3*已经消耗完，同时在反应过程中产生一个很浓的新点。将几个反应进行后处理并纯化后，将产生的那个新点进行结构确认，证实新点的结构如式Ⅲ所示即A，表明IM3*和FQs之间的偶联并没有发生，而是中间体IM3*与偶联剂生成混合酸酐后与自身的氨基发生了分子内偶联反应。经过实验表明，采用偶联剂促使IM3*与FQs生成酰胺的反应不能进行。
6、中间体IM1-2的合成
Figure BDA0002702044860000131
向反应瓶中加入PAS 20mmol、无水乙醇25mL，室温搅拌。冰浴，缓慢滴加浓硫酸50mmol，滴毕，80℃油浴回流反应，TLC监测直至反应结束。冰浴冷却，饱和碳酸钠调节pH在7-8，冷藏，抽滤，滤饼用冰水洗涤。滤液用DCM萃取(3×30mL)，收集有机相，饱和NaCl溶液洗涤。无水硫酸钠干燥，旋蒸，并与滤饼合并，柱层析，真空干燥后称重，得中间体IM1-2(白色固体)2.32g，收率为64％。
7、对氨基水杨酸的氟喹诺酮类衍生物TM6的合成
Figure BDA0002702044860000132
向反应瓶中依次加入IM3-1、HATU 1.1mmol、Et3N、IM1-2、DCM 3mL，45℃恒温磁力搅拌反应，TLC检测反应进程，反应完毕后。加入100mL DCM搅拌溶解，抽滤，滤液依次用饱和NaHCO3溶液(20mL×2)、1N HCl溶液(20mL×2)、饱和NaCl溶液(20mL×1)洗涤，无水硫酸钠干燥，旋蒸。柱层析(DCM/CH3OH＝100:1-50:1,v/v)和薄层层析，真空干燥，得目标化合物TM6。实验条件及结果如表3所示。
表3 制备TM6的实验条件及结果
Figure BDA0002702044860000133
Figure BDA0002702044860000141
8、TM6产品结构表征如下：
Figure BDA0002702044860000142
TM6-1:8-Chloro-1-cyclopropyl-7-(3-(4-((4-(ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanamido)pyrrolidin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.278.5～281.3℃；1H NMR(600MHz,DMSO-d6)δ14.55(s,1H,H-16),10.71(s,1H,H-3),10.29(s,1H,H-7),8.85(s,1H,H-17),7.98(d,J＝11.7Hz,1H,H-15),7.72(d,J＝8.7Hz,1H,H-6),7.40(s,1H,H-4),7.09(d,J＝8.8Hz,1H,H-5),4.43～4.38(m,1H,H-18),4.33(q,J＝7.0Hz,2H,H-2),3.72～3.63(m,3H,H-11 and H-12),3.39～3.36(m,2H,H-14),3.30～3.25(m,2H,H-13),2.72(t,J＝6.3Hz,2H,H-8),2.63(t,J＝6.1Hz,2H,H-9),1.33(t,J＝7.1Hz,3H,H-1),1.21～1.18(m,2H,H-19 and H-20),1.03～0.98(m,2H,H-19 and H-20).13C NMR(151MHz,DMSO-d6)δ176.32,173.26,169.59,168.94,165.20,164.38,146.85,145.79,144.24,138.48,134.05,130.04,125.19,123.62,114.09,109.27,108.27,106.36,104.23,57.17,50.45,48.56,45.29,34.27,33.91,31.36,32.19,14.67,11.38,11.25.HR MS calcd for C30H30ClFN4O8,[M+H]+ 629.1809,found 629.1817.
TM6-2:1-Cyclopropyl-7-(4-(4-((4-(ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.259.8～263.4℃；1H NMR(600MHz,DMSO-d6)δ15.20(s,1H,H-16),10.70(s,1H,H-3),10.29(s,1H,H-7),8.67(s,1H,H-17),7.93(d,J＝13.1Hz,1H,H-15),7.71(d,J＝8.7Hz,1H,H-6),7.58(d,J＝7.3Hz,1H,H-14),7.39(d,J＝1.4Hz,1H,H-4),7.08(dd,J＝8.7Hz,J＝1.4Hz,1H,H-5),4.33(q,J＝7.1Hz,2H,H-2),3.85～3.80(m,1H,H-18),3.74(s,2H,H-10 and H-11),3.69(s,2H,H-10 and H-11),3.39(s,2H,H-12 and H-13),3.30(s,2H,H-12 and H-13),2.72(t,J＝6.3Hz,2H,H-9),2.63(t,J＝6.2Hz,2H,H-8),1.34～1.30(m,5H,H-1、H-19 and H-20),1.20–1.18(m,2H,H-19 and H-20).13C NMR(151MHz,DMSO-d6)δ176.86,171.92,170.38,169.29,166.36,161.93,148.52,146.28,145.03,139.64,131.09(2C),119.28,111.43,110.72,107.54,107.30,107.07,106.28,61.50,55.36,49.68,44.87,41.30,36.35,32.00,27.75,14.52,8.07(2C).HR MS calcdfor C30H31FN4O8,[M+H]+ 595.2199,found 595.2204.
Figure BDA0002702044860000151
TM6-3:1-Cyclopropyl-7-(3-(4-((4-(ethoxycarbonyl)-3-hydroxyphenyl)amino)-N-methyl-4-oxobutanamido)piperidin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.237.9～240.1℃；1H NMR(600MHz,DMSO-d6)δ14.96(s,1H,H-16),10.67(s,1H,H-3),10.26(s,1H,H-7),8.69(s,1H,H-17),7.74(t,J＝11.3Hz,1H,H-15),7.70(d,J＝8.7Hz,1H,H-6),7.37(s,1H,H-4),7.06(d,J＝8.7Hz,1H,H-5),4.33(q,J＝7.0,2H,H-2),4.15(m,1H,H-18),3.79(s,3H,H-21),3.33(s,3H,H-10),3.19～3.07(m,1H,H-11),2.96(s,2H,H-22),2.80(s,2H,H-14),2.70～2.51(m,4H,H-8 and H-9),1.89～1.65(m,4H,H-12 and H-13),1.32(t,J＝7.0,3H,H-1),1.14～0.95(m,4H,H-19 and H-20).13CNMR(151MHz,DMSO-d6)δ177.61,171.05,170.64,170.41,169.56,166.11,161.77,156.93,155.29,150.98,146.31,139.77,134.54,131.13,121.36,110.72,107.41,107.04,106.25,63.21,55.36,54.31,53.70,52.63,50.73,41.23,32.14,30.44,27.96,25.80,14.28,9.51,9.21.HR MS calcd for C33H37FN4O9,[M+H]+ 653.2617,found 653.2619.
TM6-4:1-Cyclopropyl-7-(4-(4-((4-(ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.166.7～169.5℃；1H NMR(600MHz,DMSO-d6)δ14.94(s,1H,H-16),10.70(s,1H,H-3),10.29(s,1H,H-7),8.71(s,1H,H-17),7.78(d,J＝11.9Hz,1H,H-15),7.72(d,J＝8.7Hz,1H,H-6),7.40(s,1H,H-4),7.08(d,J＝8.5Hz,1H,H-5),4.33(q,J＝14.2,7.1Hz,2H,H-2),4.19～4.14(m,1H,H-18),3.72(s,3H,H-21),3.56～3.41(m,3H,H-14and H-10),3.33～3.24(m,3H,H-12 and H-13),3.16～3.03(m,1H,H-13),2.82～2.58(m,4H,H-8 and H-9),1.42～1.36(m,2H,H-11),1.33(t,J＝7.1Hz,3H,H-1),1.25～1.21(m,1H,H-11),1.16～1.09(m,2H,H-19 and H-20),1.06～1.00(m,2H,H-19 and H-20).13C NMR(151MHz,DMSO-d6)δ173.03,171.24,170.99,168.50(2C),163.82,149.34,131.12(2C),129.79,127.81,122.48,121.83,118.26,112.93,112.30,110.73,107.56,106.40,72.74,63.97,63.31,60.73,52.58,38.71,34.13,26.92,22.53,14.55,14.28,9.43(2C).HR MScalcd for C32H35FN4O9,[M+H]+ 639.2461,found 639.2466.
Figure BDA0002702044860000152
TM6-5:7-(4-(4-((4-(Ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.265.8～268.6℃；1H NMR(600MHz,DMSO-d6)δ15.34(s,1H,H-16),10.70(s,1H,H-3),10.29(s,1H,H-7),8.96(s,1H,H-17),7.93(d,J＝13.1Hz,1H,H-15),7.71(d,J＝8.7Hz,1H,H-6),7.39(d,J＝1.5Hz,1H,H-4),7.20(d,J＝6.9Hz,1H,H-14),7.08(dd,J＝8.7Hz,J＝1.5Hz,1H,H-5),4.59(q,J＝6.9Hz,2H,H-18),4.33(q,J＝7.1Hz,2H,H-2),3.70(d,J＝27.9Hz,4H,H-10 and H-11),3.34(d,J＝48.3Hz,4H,H-12 and H-13),2.72(t,J＝6.3Hz,2H,H-9),2.64(t,J＝6.2Hz,2H,H-8),1.42(t,J＝7.0Hz,3H,H-19),1.33(t,J＝7.1Hz,3H,H-1).13C NMR(151MHz,DMSO-d6)δ176.66,171.91,170.37,169.29,166.54,161.93,154.12,152.47,149.00,146.28,137.64,131.07,119.96,111.71,110.71,107.62,107.52,106.59,106.27,61.49,49.55(2C),44.92,41.34(2C),32.00,27.75,14.83,14.51.HR MS calcd for C29H31FN4O8,[M+H]+ 583.2199,found 583.2209.
TM6-6:7-(4-(4-((4-(Ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)-3-methylpiperazin1-yl)-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid White solid；m.p.281.4～283.3℃；1H NMR(600MHz,DMSO-d6)δ14.89(s,1H,H-16),10.70(s,1H,H-3),10.29(s,1H,H-7),8.95(s,1H,H-17),7.89(d,J＝11.6Hz,1H,H-15),7.72(d,J＝8.7Hz,1H,H-6),7.40(s,1H,H-4),7.08(d,J＝8.6Hz,1H,H-5),4.59(q,J＝3.6Hz,2H,H-18),4.33(q,J＝7.1Hz,2H,H-2),3.89～3.39(m,5H,H-10 and H-12 and H-13),3.30～2.96(m,2H,H-14),2.77(t,2H,H-8),2.62(t,J＝8.7Hz,2H,H-9),1.45(t,J＝6.9Hz,3H,H-19),1.40～1.37(m,1H,H-11),1.33(t,J＝7.1Hz,3H,H-1),1.24～1.19(m,2H,H-11).13C NMR(151MHz,DMSO-d6)δ176.03,171.96,170.40,169.29,165.98,161.93,151.70(2C),146.29(2C),131.08(2C),127.76,121.35,110.72,107.53(2C),106.27(2C),61.49,54.27,54.17,50.97,48.80,40.59,32.07(2C),16.39,14.52(2C).HR MS calcd for C30H32F2N4O8,[M+H]+ 615.2261,found 615.2272.
Figure BDA0002702044860000161
TM6-7:7-(4-(4-((4-(Ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
White solid；m.p.227.4～229.8℃；1H NMR(600MHz,DMSO-d6)δ15.11(s,1H,H-16),10.70(s,1H,H-3),10.26(s,1H,H-7),8.65(s,1H,H-17),8.01(d,J＝13.0Hz,1H,H-15),7.80(dd,J＝8.5,4.7Hz,2H,H-18 and H-19),7.71(d,J＝8.7Hz,1H,H-6),7.55(t,J＝8.5Hz,2H,H-20 and H-21),7.37(d,J＝1.4Hz,1H,H-4),7.06(dd,J＝8.7,1.4Hz,1H,H-5),6.41(d,J＝7.1Hz,1H,H-14),4.33(q,J＝14.1,7.0Hz,2H,H-2),3.65～3.61(m,2H,H-10and H-11),3.58～3.55(m,2H,H-10and H-11),3.10～3.07(m,2H,H-12 and H-13),3.05～3.03(m,2H,H-12 and H-13),2.65(t,J＝6.2Hz,2H,H-9),2.58(t,J＝5.8Hz,2H,H-8),1.32(t,J＝7.1Hz,1H,H-1).13C NMR(151MHz,DMSO-d6)δ177.18,171.89,170.30,169.29,166.17,161.93,152.50,149.20,146.27,145.46,139.66,136.68,131.07,130.36,117.84(2C),117.69(2C),111.67,111.51,110.71,107.94,107.52,107.07,106.27,61.49,49.51,44.64,41.19,38.72,31.96,27.68,14.52.HR MS calcd for C33H30F2N4O8,[M+H]+649.2104,found 649.2119.
TM6-8:7-(4-(4-((4-(Ethoxycarbonyl)-3-hydroxyphenyl)amino)-4-oxobutanoyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
White solid；m.p.260.5～262.3℃；1H NMR(600MHz,DMSO-d6)δ15.29(s,1H,H-16),10.68(s,1H,H-3),10.27(s,1H,H-7),8.97(s,1H,H-17),8.07(d,J＝13.4Hz,1H,H-15),7.70(d,J＝8.7Hz,1H,H-6),7.38(s,1H,H-4),7.07(d,J＝8.6Hz,1H,H-5),4.50(q,J＝6.9Hz,2H,H-2),4.33(q,J＝7.0Hz,2H,H-18),3.93～3.87(m,2H),3.85～3.80(m,2H),3.76～3.71(m,2H),3.69～3.64(m,2H),2.71(t,J＝6.2Hz,2H),2.63(t,J＝6.0Hz,2H),1.40(t,J＝7.0Hz,3H),1.33(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO-d6)δ176.89,171.91,170.60,169.28,166.28,161.93(2C),152.20,150.49,148.21,146.27,145.33,136.06,131.08,119.82,110.73,107.55,106.30,61.49,47.67,44.60,41.26,40.60,32.01,27.82,21.51,15.18,14.52.HR MS calcd for C28H30FN5O8,[M+H]+ 584.2151,found 584.2161.
三、对氨基水杨酸的氟喹诺酮类衍生物的生物活性检测
1、体外抗细菌活性测定
采用微量肉汤稀释法，测定化合物抑制金黄色葡萄球菌(Staphyloccocus aureusATCC 25129)、藤黄微球菌(Micrococcus luteus)、大肠杆菌(Escherichia coli ATCC25922)、鲍曼不动杆菌(Acinetobacter baumannii ATCC 19606)、沙门氏菌(SalmonellaEnteritidis ATCC 13076)和铜绿假单胞菌(Pseudomonas aeruginosa ATCC 27853)的活性(MIC值)。
取样品3.2mg，先以含5％吐温80的DMSO溶液配成母液，浓度为3.2mg/mL，再吸取200μL母液，用肉汤稀释至500μL，得浓度为1.28μg/μL的待测液。
接种保存的菌株于普通液体培养基中，置于37℃恒温摇床活化培养17h。活化后用脑心浸液肉汤(BHI)培养基分别稀释成105CFU/mL的菌悬液备用(即5mL肉汤/5μL菌)。
操作：在96孔板每一列的第一孔加入空白肉汤60μL，其余孔加入空白肉汤50μL；在每一列的第一孔加入待测液40μL，然后对待测物进行二倍稀释，即：第一孔中加入待测液后用移液枪充分吹打(至少三次以上，使待测物与肉汤充分混匀)，然后吸取50μL加入第2孔，再充分吹打后吸取50μL加入第3孔，照此重复直至第八孔，第八孔中吸取50μL弃去；此时每孔待测物浓度从上到下依次为512,256,128,64,32,16,8,4μg/mL。每一块板的最后两列作为对照，都不含待测物，一列作为细菌生长对照加入菌液，另一列作为阴性对照不加菌液。最后，在每列1-8孔中加入稀释好的菌液50μL，采取复孔测试，每块板测试5个化合物，此时每孔待测物浓度即最终浓度从上到下依次为256,128,64,32,16,8,4,2μg/mL。
将接种好的96孔板放入37℃恒温培养箱培养20-24h，观察孔内细菌生长情况。确定生长对照孔的细菌正常生长、阴性对照孔无细菌生长。观察没有细菌生长的孔中的药物浓度作为该药物对该细菌的MIC值。
对氨基水杨酸的氟喹诺酮类衍生物及中间体的体外抑菌活性测试结果见表4。
表4 化合物对6种致病菌的抑制活性(MIC值,μg/mL)
Figure BDA0002702044860000181
Figure BDA0002702044860000191
从表4中可知：PAS对六种细菌并无抑制作用，但目标化合物和阳性对照沙星的抑菌活性整体较好。对金黄色葡萄球菌，有8个化合物的MIC≤6.4μg/mL，其中，甲酯(TM3)、乙酯(TM6)类衍生物各有4个；甲酯类衍生物MIC<1μg/mL的有2个分子，其中TM3-3的MIC值达到了0.2μg/mL，乙酯类衍生物MIC<1μg/mL的也有2个分子，其中TM6-4的MIC值达到了0.4μg/mL，TM3-3与TM6-4的活性与多数阳性对照氟喹诺酮相当甚至更强；对于大肠杆菌，化合物TM3-7的MIC值为6.4μg/mL；对于藤黄微球菌，TM6-1 MIC值为1.6μg/mL、TM3-3为6.4μg/mL，强于大多数阳性对照药物氟喹诺酮。这些结果表明，对氨基水杨酸的氟喹诺酮类衍生物在抗细菌领域具有潜在的应用前景。
2、体外抗真菌活性测定
采用NCCLS推荐的微量肉汤稀释法，氟康唑为阳性对照药物，测定化合物抑制毕赤酵母菌的活性(MIC值)。
操作：
(1)-样品溶液的制备：用万分之一天平在干燥室内精确称取样品3.2mg于2mL PE管中，移液枪向PE管中加入1mL DMSO，溶解为澄清透明液体，配制成3.2mg/mL的溶液，封口膜封口后，冰柜避光保存。对于部分难溶的化合物使用DMSO/吐温-80＝200/1(v/v)代替DMSO，吐温-80为助溶剂。
(2)待测液的配制：用适宜的溶剂及稀释剂将待测物配制成浓度为3.2mg/mL的储备液，再吸取320μL储备液，加入沙氏培养基至总体积为0.5mL，其浓度为2048μg/mL，即为待测液B。
(3)菌悬液的制备：接种保存的菌株于沙氏琼脂液体培养基中，置于30℃恒温摇床活化培养24h。活化后用蒸馏水洗涤琼脂表面菌落，后用沙氏培养基稀释成105CFU/mL的菌悬液备用。
(4)加样操作：无菌条件下，在96孔板每个孔加入沙氏培养基50μL；在第一排的第一孔、第二孔加入待测液B 50μL，经过此二倍稀释后，浓度为1024μg/mL；第一孔、第二孔用移液枪充分吹打，使待测物与培养基充分混匀，然后吸取50μL加入第二排的第一孔、第二孔，再吹打使之充分混匀，照此重复直至第八排，第八排每孔吸取50μL弃去；此时每孔待测物浓度从高至低(从上至下)依次为1024,512,256,128,64,32,16,8μg/mL；再在96孔板每孔中加入稀释好的菌液50μL，此时每孔待测物浓度即最终待测物浓度从高至低(从上至下)依次为512,256,128,64,32,16,8,4μg/mL。
5)培养和结果判定：将接种好的96孔板放入30℃恒温培养箱培养24、30h。培养完成后取出，观察孔内细菌生长情况。确定空白无药对照(阴性对照)孔的细菌正常生长和阳性对照(培养基+菌株+阳性药物)孔无细菌生长，所测试的结果才算正常。肉眼观察没有细菌生长的孔中的药物浓度作为该药物对该细菌的MIC。
对氨基水杨酸的氟喹诺酮类衍生物及中间体的体外抑真菌活性测试结果如表5所示。
表5 化合物对毕赤酵母菌的抑制活性(MIC值,μg/mL)
Figure BDA0002702044860000201
分析表5可知：母核PAS、IM1-1和IM1-2的MIC>256μg/mL，对毕赤酵母菌几乎没有抑制活性，但测试的目标化合物对毕赤酵母菌的抑制活性都强于母体PAS、PAS的甲酯(IM1-1)及其乙酯(IM1-2)；培养24h，整体活性很好。测试的16个目标分子的MIC值都在4～256μg/mL之间，有10个分子的MIC值在4～128μg/mL之间，有8个分子的MIC≤4μg/mL，与阳性对照药物氟康唑的MIC值相同；从构效关系分析，乙酯(TM6)类衍生物大于甲酯(TM3)类衍生物，8个TM6目标分子对毕赤酵母菌株的抑制活性强于或相当于氟康唑。这些结果证明，对氨基水杨酸的氟喹诺酮类衍生物具有抗真菌活性。
3、抗结核活性测定
试验菌株：耻垢分枝杆菌Mycolicibacterium smegmatis(strain ATCC 700084/mc(2)155)
测定耻垢分枝杆菌所用培养基为7H9培养基；所用试剂、工具均需提前灭菌；所有操作应在超净台的无菌条件下进行。
待测液的配制：准确称取待测样品10.0mg，用适宜的溶剂及稀释剂配成浓度为1.0μg/μL的待测液。取1.0μg/μL的待测液，用一次性过滤器(过滤直径为13～30mm)过滤得待测液C。
操作：在96孔板的第1列加入培养好的野生型的耻垢分枝杆菌菌液200μL，第2-12列分别加入100μL菌液；第1列的首孔加入待测液C10μL，然后对用移液枪充分吹打(至少3次以上，使待测物与菌液充分混匀)，然后吸取100μL加入第2列第一孔，充分吹打使之混匀，再从第2列第一孔吸取100μL加入第3列第一孔，，照此重复直至第11列；第12列为100μL菌液的阴性对照。此时每孔待测物浓度从左到右依次为50,25,12.5,6.25,3.12,1.56,0.78,0.39,0.19,0.09,0.05μg/mL，每一块板的最后一列为阴性对照。将接种好的96孔板放入37℃恒温培养箱培养3d，观察孔内细菌生长情况。确定空白无药对照孔的耻垢分枝杆菌正常生长、阴性对照孔无菌生长。将肉眼观察到的没有耻垢分枝杆菌生长的孔中的药物浓度作为该药物对该细菌的MIC。每株菌做3个重复，如出现多处跳孔，则不应报告结果，需重复试验。
将对氨基水杨酸的氟喹诺酮类衍生物及中间体对耻垢分枝杆菌进行MIC的测定。测定过程均设有空白对照、阴性对照、阳性对照，结果如表6所示。
表6化合物对抗耻垢分枝杆菌的抑制活性(MIC值)
Figure BDA0002702044860000211
Figure BDA0002702044860000221
从表6中分析可知，中间体IM1-1和IM1-2的MIC值均为0.19μg/mL，强于异烟肼、利福平和多数氟喹诺酮阳性药物，证明对氨基水杨酸的氟喹诺酮类衍生物的中间体具有抗结核能力。
4、抗柑橘褐斑病菌、炭疽病菌和溃疡病菌生物活性研究(初筛)
(1)药剂母液的配制：用适宜的溶剂及稀释剂将药剂母液稀释至所需的浓度(样品质量为1.0mg，先配成药剂母液1.0mg/1mL＝1.0mg/mL。每种药剂设置2个稀释浓度，0.001mg/mL(即稀释1000倍)和0.004mg/mL(即稀释250倍))。
(2)操作
药剂培养基配制：稀释1000倍的药剂培养基配制：取5μL药剂与5mL热PDA培养基在10mL离心管中充分混匀；稀释250倍的药剂培养基配制：取20μL药剂与4980μL热PDA培养基在10mL离心管中充分混匀。对照组：以不加药剂的PDA培养基和加入咪鲜胺的药剂培养基(稀释1000和稀释250倍)作为对照。接菌：将配置好的药剂培养基倒入24孔板内，每株菌每种药每个浓度倒一个孔，并做好编号的标记。挑取28℃培养7d的菌株的菌丝，接种于每孔正中央。培养：将24孔板放于28℃、光照16h的培养箱内培养48h。测量：运用十字交叉法测量菌落直径。计算：抑制率％＝(CK菌落直径值-测量菌落直径值)×100％/CK菌落直径值。筛选：将不同药剂抑制率同咪鲜胺药剂的抑制率进行比较。
对氨基水杨酸的氟喹诺酮类衍生物及中间体抗柑橘病菌的测定结果如表7和8所示。
表7 化合物对柑橘真菌病菌的抑制活性(初筛结果)
Figure BDA0002702044860000231
表8 化合物抗柑橘溃疡病菌的活性结果
Figure BDA0002702044860000232
Figure BDA0002702044860000241
从表8数据可以看出，母体PAS在上述测试浓度下，其抑制率分别为9.44％和6.27％，活性很弱。在1.6μg-/mL测试浓度下，目标分子TM6抑制活性高于40％的分子有2个，其抑制活性强于PAS；在0.64μg/mL测试浓度下，抑制率高于40％的分子有1个。证明了对氨基水杨酸的氟喹诺酮类衍生物在抗柑橘病菌领域具有进一步研究的潜质。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。

Claims (10)

1.式Ⅰ所示的对氨基水杨酸的氟喹诺酮类衍生物，其消旋体、立体异构体、互变异构体、氮氧化合物或药学上可接受的盐：
Figure FDA0002702044850000011
式Ⅰ中，
X选自：乙基、4-FC6H4或
Figure FDA0002702044850000012
Z选自：C、N或CR1，R1为H、烷氧基或卤素；
Y选自：
Figure FDA0002702044850000013
R2和R3独立地选自为H或C1-C3烷基，m为1或2；
L选自：-CO(CH2)nCO-，n为2，3或4；
R选自：C1-C6烷基。
2.根据权利要求1所述对氨基水杨酸的氟喹诺酮类衍生物，其特征在于，所述式Ⅰ中，
Z选自：C、N或CR1，R1为H、C1-C3烷氧基、F或Cl；
Y选自：
Figure FDA0002702044850000014
R2和R3独立地选自为H或甲基，m为1或2；
L选自：-CO(CH2)nCO-，n为2，3或4；
R选自：C1-C3烷基。
3.根据权利要求2所述对氨基水杨酸的氟喹诺酮类衍生物，其特征在于，所述式Ⅰ中，
Z选自：C、N或CR1，R1为H、甲氧基、F或Cl；
L选自：-CO(CH2)2CO-；
R选自：甲基或乙基。
4.根据权利要求3所述对氨基水杨酸的氟喹诺酮类衍生物，其特征在于，式Ⅰ所示的对氨基水杨酸的氟喹诺酮类衍生物为以下化合物中的任一种：
Figure FDA0002702044850000021
Figure FDA0002702044850000031
5.如权利要求1至权利要求4任一所述对氨基水杨酸的氟喹诺酮类衍生物的制备方法，其特征在于，包括以下步骤：
将对氨基水杨酸羧基进行酯化，制得中间体IM1；
Figure FDA0002702044850000032
将氟喹诺酮与linker试剂反应，制得中间体IM3；
Figure FDA0002702044850000033
将中间体IM1与中间体IM3偶联，制得对氨基水杨酸的氟喹诺酮类衍生物；
Figure FDA0002702044850000034
式中，X，Z，Y，L和R的定义均与权利要求1～3任一所述的对氨基水杨酸的氟喹诺酮类衍生物结构式中X，Z，Y，L和R的定义相同。
6.根据权利要求5所述对氨基水杨酸的氟喹诺酮类衍生物的制备方法，其特征在于，包括以下步骤：
A、将对氨基水杨酸在酸作用下反应与醇反应，制得中间体IM1；所述醇为甲醇或乙醇；所述酸为硫酸；
B、将氟喹诺酮与linker试剂在有机溶剂中、碱作用下进行氨基酰化，制得中间体IM3；所述有机溶剂为二氯甲烷、氯仿、丙酮、乙酸乙酯、四氢呋喃或乙醚；所述碱为碳酸钾、碳酸钠、三乙胺或碳酸氢钠；
C、将中间体IM1与中间体IM3在有机溶剂、碱及偶联剂作用下偶联，制得对氨基水杨酸的氟喹诺酮类衍生物；所述有机溶剂为二氯甲烷、氯仿、乙腈、四氢呋喃或N,N-二甲基甲酰胺；所述碱为碳酸氢钠、三乙胺、氢氧化钠、甲醇钠或碳酸钾；所述偶联剂为二环己基碳二亚胺(DCC)、1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)或O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)。
7.如权利要求5所述制备方法制得的中间体IM1，即
Figure FDA0002702044850000041
8.如权利要求5所述制备方法制得的中间体IM1，即
Figure FDA0002702044850000042
在抗结核药物中的应用。
9.如权利要求1至权利要求4任一所述对氨基水杨酸的氟喹诺酮类衍生物在抗细菌药物中的应用。
10.如权利要求1至权利要求4任一所述对氨基水杨酸的氟喹诺酮类衍生物在抗真菌药物中的应用。
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