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CN114478486B - 以对氨基水杨酸为母核的三分子缀合物、中间体、制备方法及用途 - Google Patents

以对氨基水杨酸为母核的三分子缀合物、中间体、制备方法及用途 Download PDF

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CN114478486B
CN114478486B CN202210106754.XA CN202210106754A CN114478486B CN 114478486 B CN114478486 B CN 114478486B CN 202210106754 A CN202210106754 A CN 202210106754A CN 114478486 B CN114478486 B CN 114478486B
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aminosalicylic acid
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范莉
杨大成
任艳会
谢建平
许峻旗
代乐平
毛丹
杨茜
周成合
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Southwest University
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Abstract

本发明公开了式I所示的以对氨基水杨酸(PAS)为母核的三分子缀合物，是由PAS、异烟酸和氟喹诺酮这三种结构单元缀合而成；经抗人致病菌活性测试，本发明合成的三分子缀合物均具有一定的抗细菌活性，尤其存在对结核分枝杆菌、沙门氏菌、铜绿假单胞菌、金黄色葡萄球菌具有高抑菌活性的多个分子，同时溶血性测试验证了分子的安全性，具有进一步开发研制抗细菌药物尤其是抗结核药物的潜力。

Description

以对氨基水杨酸为母核的三分子缀合物、中间体、制备方法及 用途
技术领域
本发明属于药物合成技术领域，涉及一类以对氨基水杨酸(p-aminosalicylicacid,PAS)为母核的三分子缀合物、中间体、制备方法及制药用途。
背景技术
结核病(Tuberculosis,TB)是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)引起的慢性致死性传染性疾病。在冠状病毒(COVID-19)大流行之前，结核病是单一传染病的主要死亡原因，排名高于艾滋病。至今，TB依然是全球的公共健康问题。
世界卫生组织(World health organization,WHO)根据抗结核药物作用效果及副作用的大小将其分为一线和二线抗结核治疗药物。一线TB药物链霉素(Streptomycin,SM)、异烟肼(Isoniazid,INH,H)、吡嗪酰胺(Pyrazinamide,PZA,Z)、利福平(Rifampicin,RIF,R)和乙胺丁醇(Ethambutol,EMB,E)疗效显著、副作用较少、能够同时杀灭快速增殖期和慢速繁殖期的结核杆菌，是TB治疗的首选品种。二线TB药物种类较多，喹诺酮类(FQS)、大环内酯类、吩噻嗪类、氨基糖苷类、噁唑烷酮类、环丝氨酸、PAS是其代表，但其副作用相对更多、疗效相对较差。由于TB的特殊性，敏感TB的治疗总是采用多药同时服用的联合治疗方案，大约85％的TB患者采用包含利福平的2HRZE+4HR 6月治疗方案，一般能够治疗成功。虽然敏感TB的治疗取得了巨大成就，但耐药结核病(Drug-resistant Tuberculosis,DR-TB)，包括耐多药结核病和广泛耐药结核病，在世界范围内依然是最严峻的挑战。多药耐药且耐药率高为复治肺结核患者主要特征，即使采取WHO推荐的多种药物联合治疗方式，还是存在治疗周期很长、产生耐药等临床问题，原因之一是患者依从性差进而产生耐药性。
发明内容
多靶点药物设计策略，是目前解决复杂疾病尤其是多靶点疾病治疗的新思路。药效团连接法，可将多种作用靶点的药物引入单一分子之中，实现多靶点药物的设计。
将两种或多种抗结核分子偶联为单一分子，既可能具有同样疗效又可减少单次服药量，相比WHO推荐的多药同时服用的联合治疗方案，可以改善患者的依从性差的问题，进而减少耐药性的产生，是很有价值的药物研究课题。
INH是一种前药，通过被动运输进入MTB内部，由MTB的过氧化氢酶-过氧化物酶(KatG)激活，形成异烟酰基自由基，随后与NAD+结合，形成IN-NAD加合物，进而抑制烯酰-酰基载体蛋白还原酶(InhA)，干涉分枝菌酸的合成，从而破坏细菌细胞壁。
抗菌药物FQs对敏感TB和DR-TB都有很好的治疗效果，与其它抗TB药物联用的疗效比其单用更为显著。FQs药物靶向DNA解旋酶，抑制MTB复制周期，导致细胞死亡。
PAS适用于结核分枝杆菌所致的肺及肺外结核病，必须与其他抗结核药合用。与SM或INH合用时能延缓结核杆菌对二者耐药性的产生。PAS有羧基、羟基、氨基三个官能团，不仅可作为多靶点药物的连接子(linker)，而且可作为一种抗结核药物，以其为母核设计分子，既可将三种药物片段缀合在同一分子(3-in-1)中，又可将目标分子的分子量降低，在降低合成难度的优势下还可能提高整个分子的成药性，具有潜在的研究前景。
有鉴于此，本发明的目的在于以PAS为母核，将PAS衍生为对应羧酸酯，留下氨基和羟基与异烟酸(INA)和FQs连接，设计合成一类三分子缀合物，并对其抗菌活性进行测试。
作为一种尝试，选择羟基连接FQs、氨基连接INA，由此设计了目标分子模式(见图1中Mode of target molecule)，其中Linker1连接INA的羧基和PAS的氨基，Linker2连接PAS的羟基和FQs的胺基。Linker的选择是药效团拼接法的重要内容。合适的linker必须拥有将两个或多个片段连接的功能，同时满足分子量尽可能小、分子刚柔性适度、代谢片段无毒等要求。基于分子无毒、结构简单、可连接羟基和胺基等设想，本发明选择卤代酰氯作为Linker1和Linker2的试剂，据此设计了目标分子(见图1中Target molecule)。基于分子量尽可能小的要求，本发明进一步设计了Linker1为乙酰基、Linker2为丙酰基的目标分子TM1和TM2(见图1)。通过合成路线设计和反应条件探索，本发明成功合成了16个尚未报道的新分子，经抗人致病菌活性测试，这些分子均具有一定的抗菌活性，尤其存在对结核分枝杆菌、沙门氏菌、铜绿假单胞菌、金黄色葡萄球菌具有高抑菌活性的多个分子，同时溶血性测试验证了分子的安全性。为此，本发明最终提供如下技术方案：
1.式I所示的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐：
式I中，R为甲基或乙基；
X为环丙基、乙基或4-卤代苯基；
Y为---表示与羰基的连接端；/>表示与芳环的连接端；
Z为N或C-R1；R1为氢、卤素或甲氧基。
进一步，X为环丙基、乙基或4-氟代苯基；R1为氢、氟、氯或甲氧基。
进一步，式I所示的以对氨基水杨酸为母核的三分子缀合物为以下化合物中的任一种：
进一步，式I所示的以对氨基水杨酸为母核的三分子缀合物为以下化合物中的任一种：TM1a、TM1b、TM1f、TM1h、TM2a、TM2b、TM2c、TM2h。
2.式II所示的中间体或其药学上可接受的盐，用于制备式I所示的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐：
式II中，R为甲基或乙基。
3.式I所示的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐的制备方法，包括以下步骤：
a.将PAS与醇ROH在浓硫酸催化下于60-70℃加热反应，制得中间体IM1；
b.将中间体IM1和氯乙酰氯在碳酸氢钠存在下、于二氯甲烷(DCM)中冰浴搅拌反应，制得中间体IM2；
c.将中间体IM2和INA在三乙胺存在下、于二甲基亚砜(DMSO)中60℃油浴搅拌反应，制得中间体IM3；
d.将FQs和3-氯丙酰氯在碳酸氢钠存在下、于DCM中冰浴搅拌反应，制得中间体IM4；
e.将中间体IM3和IM4在碳酸钾、催化剂NaI存在下、于N,N-二甲基甲酰胺(DMF)中60℃油浴搅拌反应，即制得式I所示的以对氨基水杨酸为母核的三分子缀合物；
醇ROH、中间体IM1、IM2和IM3中，R都具有式I中的定义；
FQs和中间体IM4中，X、Y和Z都具有式I中的定义。
4.式I所示的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐在制备抗细菌药物中的应用。
进一步，所述抗细菌药物是抗结核分枝杆菌、金黄色葡萄球菌、藤黄微球菌、大肠杆菌、鲍曼不动杆菌、沙门氏菌和铜绿假单胞菌中一种或多种的药物。
5.式II所示的中间体或其药学上可接受的盐在制备抗细菌药物中的应用。
进一步，所述抗细菌药物是抗结核分枝杆菌、金黄色葡萄球菌、藤黄微球菌、大肠杆菌、鲍曼不动杆菌、沙门氏菌和铜绿假单胞菌中一种或多种的药物。
除另有说明外，本发明中的术语“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“卤素”指F、Cl、Br和I。
本发明的有益效果在于：本发明采用药物片段拼接原理，将PAS、INA与FQs通过linker拼接成单一分子，设计合成了一类以PAS为母核的三分子缀合物。经抗人致病菌活性测试，这些分子均具有一定的抗细菌活性，尤其存在对结核分枝杆菌、沙门氏菌、铜绿假单胞菌、金黄色葡萄球菌具有高抑菌活性的多个分子，同时溶血性测试验证了分子的安全性，具有进一步开发研制抗细菌药物尤其是抗结核药物的潜力。
附图说明
图1为目标分子TM1/TM2的设计图。
图2为目标分子TM1/TM2的合成路线图。
图3为目标分子TM1a/TM2a的溶血性测试结果。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚，下面将对本发明的优选实施例进行详细的描述。
主要化学试剂及仪器
PAS(上海泰坦有限公司,98％)；INA、浓硫酸、甲醇、乙醇、碳酸氢钠、碳酸钾(重庆川东化工有限公司)；克林沙星(CLX)、环丙沙星(CIP)、沙拉沙星(SAR)、依诺沙星(ENX)、巴洛沙星(BAL)、加替沙星(GAT)(郑州克尔泰生化科技有限公司,>95％)；诺氟沙星(NOR)、洛美沙星(LOM)(上海达瑞精细化工有限公司,AR)；氯乙酰氯、3-氯丙酰氯(重庆钛新化工有限公司)；其余试剂均为市售化学纯或分析纯产品，未经纯化直接使用。
核磁共振仪(Bruker,ADVANCEⅢTM 600MHz,TMS为内标)；高分辨质谱仪(QTOF-MS,Bruker ImpactⅡ,Bremen,Germany)；熔点测定仪(X-6,北京福凯仪器有限公司)。
1目标分子TM的合成
a.中间体IM1a/IM1b的合成
以PAS与甲醇(MeOH)制备IM1a为例，进行了此步反应条件(催化剂种类及用量、反应温度等)探索实验(见表1)。
表1中间体IM1a的合成反应条件探索实验
经过探索，此步反应最佳条件为：以浓硫酸为催化剂，PAS与浓硫酸的投料摩尔比为1:2，60-70℃回流反应。
按照上述最佳反应条件，将PAS与甲醇/乙醇(EtOH)在浓硫酸催化下加热反应，制得中间体IM1a/IM1b。合成实验结果见表2。
操作示例：于100mL圆底烧瓶中加入PAS 1.53g(10mmol)、甲醇/乙醇10mL，室温搅拌，缓慢滴加浓硫酸1.06mL(20mmol)，滴毕，油浴回流反应，薄层色谱(TLC)监测至反应结束，冰浴冷却，饱和碳酸钠溶液调节pH＝8-9，析出大量固体，抽滤，滤饼用饱和NaCl溶液洗涤，干燥，即得中间体IM1a/IM1b，灰白色固体，m.p.分别为100.3-104.0℃、113.2-113.9℃。
表2中间体IM1a/IM1b的合成实验结果
b.中间体IM2a/IM2b的合成
将中间体IM1a/IM1b和氯乙酰氯在碳酸氢钠(缚酸剂)存在下、于DCM中冰浴搅拌反应，制得中间体IM2a/IM2b。合成实验结果见表3。
操作示例：于100mL反应瓶中加入IM1a/IM1b(10mmol)、10mL DCM，室温搅拌，加入NaHCO3(30mmol,2.522g)，继续搅拌，冰浴冷却，滴加氯乙酰氯(12mmol,1mL)，滴毕，继续冰浴搅拌反应，TLC监测至反应结束，旋除DCM，加20mL水，抽滤，滤饼依次用饱和NaCl溶液(15mL×3)、水(15mL×3)洗涤，真空干燥，即得中间体IM2a/IM2b，白色固体，m.p.分别为180.7-181.5℃、189.9-190.7℃。
表3中间体IM2a/IM2b的合成实验结果
c.中间体IM3a/IM3b的合成
以IM2a和INA反应制备IM3a为例，对此步反应条件(碱的种类、溶剂、反应温度)进行了探索实验(见表4)。
表4中间体IM3a的合成反应条件探索实验
经过探索，此步反应最佳条件为：以三乙胺(Et3N)为碱，DMSO为溶剂，60℃反应。
按照上述最佳反应条件，将中间体IM2a/IM2b和INA在Et3N存在下、于DMSO中60℃油浴搅拌反应，制得中间体IM3a/IM3b。合成实验结果见表5。
操作示例：于100mL反应瓶中加入IM2a/IM2b(5mmol)、5mL DMSO，室温搅拌，加入Et3N(7.5mmol)，继续搅拌0.5h，加入INA(7.5mmol,0.931g)，60℃油浴搅拌反应，TLC监测至反应结束，加水，析出固体，抽滤，滤饼依次用饱和NaCl溶液(15mL×3)、水(5mL×3)洗涤，真空干燥，得粗品，柱层析(PE:EA＝5:1～1:1,v/v)纯化，即得中间体IM3a/IM3b，m.p.分别为207.3-208.0℃、186.5-187.3℃。
表5中间体IM3a/IM3b的合成实验结果
d.中间体IM4a～IM4h的合成
将FQs(CLX/NOR/CIP/SAR/ENX/BAL/LOM/GAT)和3-氯丙酰氯在碳酸氢钠(碱)存在下、于DCM中冰浴搅拌反应，制得中间体IM4。合成实验结果见表6。
操作示例：于100mL圆底烧瓶中加入FQs(10mmol)、DCM(20mL)，室温搅拌均匀，加入碾细的碳酸氢钠(40mmol)，继续搅拌均匀，移至0℃冰盐浴，缓慢滴加3-氯丙酰氯(25mmol)的DCM(2.5mL)溶液，约1h滴加完毕，继续冰浴搅拌反应，TLC监测至反应结束，加入饱和NaCl溶液20mL，用2N HCl调节pH＝2-3，静置分层，分液，收集有机相，干燥除水，旋除溶剂，得固体粗品，加入乙酸乙酯(EA)15mL，搅拌30min，加入石油醚(PE)40mL进行分散，静置，抽滤，TLC监测固体，如发现存在杂点，重复多次进行分散，最后真空干燥，即得中间体IM4；当FQs为BAL和GAT时，得油状粗品，加20mL DCM重结晶，析出黄色固体，抽滤，干燥，得纯品。
表6中间体IM4a～IM4h的合成实验结果
e.目标分子TM1/TM2的合成
以IM3a和IM4a反应制备TM1a为例，对此步反应条件(溶剂和碱的种类、反应温度等)进行了探索实验(见表7)。
表7目标分子TM1a的合成反应条件探索实验
注：*反应加入催化量的NaI。
经过探索，此步反应最佳条件为：以K2CO3为碱，DMF为溶剂，60℃反应，投料摩尔比控制在IM3:IM4:K2CO3＝1:1.2:1.5。
按照上述最佳反应条件，将中间体IM3a/IM3b和IM4在K2CO3、NaI(催化剂)存在下、于DMF中60℃油浴搅拌反应，制得目标分子TM1/TM2。合成实验结果见表8。
操作示例：于100mL反应瓶中加入IM3a/IM3b(1mmol)、2mL DMF，室温搅拌，加入K2CO3(1.5mmol,0.207g)，继续搅拌0.5h，加入IM4(1.2mmol)、NaI(0.01mmol)，继续搅拌0.5h，60℃油浴搅拌反应，TLC监测至反应结束，加入冰冷的饱和NaCl溶液，2N HCl溶液调节pH＝3-4，析出固体，冷藏，抽滤，滤饼依次用饱和NaCl溶液(10mL×1)、冰水(15mL×2)洗涤，真空干燥，得粗品，柱层析(DCM:CH3OH＝150:1～20:1,v/v)纯化，部分化合物还经薄层层析(DCM:CH3OH＝50:1,v/v)纯化，即得目标化合物TM1/TM2。
表8目标分子TM1/TM2的合成实验结果
中间体IM3a/IM3b的结构式及结构表征数据如下：
IM3a:白色固体,m.p.:207.3-208.0℃.1H NMR(600MHz,DMSO-d6)δ10.61(s,1H),8.71(d,J＝5.6Hz,2H),7.74(d,J＝5.8Hz,2H),7.68(d,J＝8.5Hz,1H),7.54(s,1H),7.19(d,J＝8.3Hz,1H),5.02(s,2H),3.87(s,3H).
IM3b:白色固体,m.p.:186.5-187.3℃.1H NMR(600MHz,DMSO-d6)δ10.41(s,1H),8.77(d,J＝5.7Hz,2H),7.81(d,J＝5.8Hz,2H),7.76(d,J＝8.7Hz,1H),7.41(d,J＝1.5Hz,1H),7.12(d,J＝1.6Hz,1H),5.01(s,2H),4.35(q,J＝7.1Hz,2H),1.33(t,J＝12.7,5.6Hz,3H).
目标分子TM1/TM2的结构式及结构表征数据如下：
TM1a:白色固体,m.p.:228.3～229.2℃.1H NMR(600MHz,DMSO-d6)δ14.51(s,1H,),10.61(s,1H),10.55(s,1H),8.88–8.81(m,2H),7.94(d,J＝11.7Hz,1H),7.91(d,J＝5.6Hz,2H),7.75(d,J＝8.7Hz,1H),7.35(d,J＝1.1Hz,1H),7.09(d,J＝7.4Hz,1H),5.73(dd,J＝10.5,1.8Hz,2H),5.01(s,2H),4.41(d,J＝3.3Hz,1H),4.02(dt,J＝20.6,10.4Hz,1H),3.87(s,3H),3.76(s,3H),3.35(s,4H),2.08(d,J＝7.4Hz,1H),1.20(dd,J＝13.1,6.9Hz,3H),1.01(s,2H).13C NMRδ176.59,172.45,169.15,166.09,165.56,165.14,164.89,161.81,156.91,155.24,153.12,151.28,145.14,143.85,143.76,138.31,136.80,128.60,127.98,123.13,120.30,110.98,108.41,108.17,106.85,64.14,61.59,60.21,55.27,46.40,41.99,30.47,21.44,19.10,14.45,11.29.HR MS calcd for C36H33ClFN5O10,[M+H]+:750.1973,found:750.1972.
TM1b:白色固体,m.p.:216.2-217.0℃.1H NMR(600MHz,DMSO-d6)δ11.13(s,1H,H-22),10.64(s,1H),10.57(s,1H),9.97(s,1H),8.86(d,J＝3.8Hz,2H),7.92(d,J＝4.2Hz,2H),7.76(d,J＝8.7Hz,1H),7.72(d,J＝8.1Hz,1H),7.37(s,1H),7.11(d,J＝8.6Hz,1H),5.68(s,2H),5.00(d,J＝28.9Hz,2H),4.23(t,J＝6.4Hz,2H),4.03(d,J＝5.7Hz,1H),3.88(s,3H),3.37(s,9H),1.65(t,J＝7.3Hz,3H).13C NMRδ176.58,172.15,169.39,166.06,165.50,165.08,163.69,161.63,153.15,148.88,146.24,145.44,145.16,143.86,143.04,138.33,131.34,128.66,127.93,120.32,111.12,111.02,108.38,108.19,106.89,64.21,62.49,52.67,51.10,46.38,42.00,35.77,30.49,19.11,11.31.HR MS calcd forC35H34FN5O10,[M+Na]+:7 726.2182,found:726.2164.
TM1c:白色固体,m.p.:234.2-235.1℃.1H NMR(600MHz,DMSO-d6)δ15.19(s,1H,H-23),10.62(s,3H,H-5),10.57(s,2H,H-19),8.85(d,J＝4.9Hz,2H,H-9and H-10),8.66(s,1H,H-17),7.91(d,J＝5.4Hz,2H,H-7and H-8),7.75(d,J＝8.7Hz,1H,H-2),7.57(d,J＝6.9Hz,1H,H-3),7.35(s,1H,H-18),7.09(d,J＝8.6Hz,1H,H-4),5.01(s,2H,H-12),4.23(s,4H,H-6and H-11),3.87(s,3H,H-1),3.81(t,J＝16.1Hz,2H,H-14),3.42(s,4H,H-13and H-15),3.36(s,3H,H-16and H-20),1.33(d,J＝6.4Hz,1H,H-21),1.21(d,J＝30.7Hz,2H,H-22),0.88–0.79(m,1H,H-21).13C NMRδ176.57,172.14,169.14,168.53,166.04,165.49,165.08,163.68,161.81,155.24,153.13,148.87,146.24,145.44,145.16,143.03,138.31,131.24,130.94,128.64,127.93,110.98,108.38,108.18,106.85,65.47,64.19,62.48,61.57,61.52,55.32,41.99,35.77,30.49,14.46,11.31.HR MS calcd for C36H34FN5O10,M+H]+:716.2362,found:716.2359,[M+Na]+:738.2182,found:738.2179.
TM1d：白色固体,m.p.:207.3-208.0℃.1H NMR(600MHz,DMSO-d6)δ15.11(s,1H),10.63(s,1H),10.57(s,1H),8.85(d,J＝5.3Hz,2H),8.64(s,1H),7.99(d,J＝13.0Hz,2H),7.91(d,J＝5.4Hz,2H),7.83–7.70(m,2H),7.53(t,J＝8.4Hz,1H),7.35(s,1H),7.09(d,J＝8.6Hz,2H),5.74(s,2H),5.01(s,2H),3.87(s,3H),3.74–3.54(m,2H),3.41(d,J＝24.9Hz,8H).13C NMRδ176.61,172.49,169.15,166.11,165.60,165.16,164.90,161.79,156.90,155.23,153.13,151.27,145.13,143.85,143.76,138.31,136.80,131.92,131.27,129.09,128.95,128.57,128.04,123.51,123.14,120.29,111.11,110.98,108.42,108.14,106.85,64.13,61.60,55.26,41.99,30.46,21.44,19.09,14.45.HR MS calcd for C39H33F2N5O10,[M+H]+:770.2268,found:770.2269.
TM1e：白色固体,m.p.:213.6-214.5℃.1H NMR(600MHz,DMSO-d6)δ15.30(s,1H),10.62(s,1H),10.57(s,1H),8.96(s,1H),8.85(d,J＝4.4Hz,2H),8.07(d,J＝13.3Hz,1H),7.91(d,J＝4.4Hz,2H),7.74(d,J＝8.7Hz,1H),7.35(s,1H),5.01(s,2H),4.56–4.42(m,2H),3.87(s,3H),3.77(d,J＝35.3Hz,3H),3.43(s,10H),1.40(t,J＝6.8Hz,3H).13C NMRδ176.60,172.16,169.14,166.06,165.54,165.10,163.69,161.80,155.24,153.15,148.88,146.24,145.44,145.15,143.01,131.26,129.10,128.62,127.98,111.26,110.99,108.40,108.17,106.86,65.48,64.19,62.46,61.58,42.00,35.76,30.47,19.10,14.46,11.30.HRMS calcd for C34H33FN6O10,[M+H]+:705.2314,found:705.2315.
TM1f:黄色固体,m.p.:297.9-298.8℃.1H NMR(600MHz,DMSO-d6)δ14.94(s,1H),10.62(s,1H),8.86(d,J＝4.5Hz,1H),8.69(s,2H),7.91(d,J＝4.5Hz,2H),7.74(d,J＝11.9Hz,4H),4.56(s,2H),4.17(s,3H),4.03(dd,J＝14.3,7.2Hz,2H),3.87(s,3H),3.79(s,4H),3.14(dd,J＝28.2,10.4Hz,3H),3.00(s,3H),2.92(d,J＝14.52,2H),2.82(m,2H),1.90(Hz,2H),1.22–1.14(m,2H).13C NMRδ176.74,169.71,169.39,166.05,162.76,161.63,155.35,151.32,150.76,146.43,145.17,139.74,139.66,136.81,134.49,131.35,131.04,129.69,127.62,123.12,121.41,121.35,111.00,107.03,106.86,64.16,63.23,63.19,60.20,52.67,51.00,41.28,36.61,30.45,27.29,25.79,14.53,9.49,9.27.HR MS calcdfor C39H40FN5O11,[M+Na]+:796.2601,found:796.2608.
TM1g:淡黄色固体,m.p.:209.5-210.3℃.1H NMR(600MHz,DMSO-d6)δ15.08(s,1H),10.61(s,1H),9.95(s,1H9),8.93(d,J＝8.6Hz,2H),8.64(s,1H),7.72(d,J＝8.7Hz,1H),7.87(d,J＝8.7,2H),7.79(s,1H),7.53(t,J＝8.6,1.7Hz,1H),5.72(d,J＝10.7Hz,2H),4.59(d,J＝3.2Hz,8H),3.87(s,3H),3.51(d,J＝9.7Hz,2H),3.36(d,J＝9.6Hz,3H),1.45(t,J＝6.7Hz,6H).13C NMRδ176.61,172.18,169.39,166.08,165.56,163.69,161.62,153.16,148.88,146.24,145.44,145.14,143.01,138.33,131.36,128.62,128.00,111.29,111.12,111.03,110.97,108.40,108.16,106.99,106.90,65.49,64.20,62.45,52.68,42.00,41.05,35.75,30.47,19.10,13.95,11.30.HR MS calcd for C36H35F2N5O10,[M+H]+:736.2425,found:736.2437.
TM1h:黄色固体,m.p.:225.6-226.3℃.1H NMR(600MHz,DMSO-d6)δ14.93(s,1H),10.63(s,1H),10.57(s,1H),8.85(d,J＝4.3Hz,2H),8.72(s,1H),7.91(d,J＝4.3Hz,2H),7.76(d,J＝6.2Hz,1H),7.35(s,1H),7.09(d,J＝8.5Hz,1H),5.73(d,J＝13.6Hz,4H),5.01(s,2H),4.21(dd,J＝24.5,17.9Hz,1H),3.87(s,3H),3.72(s,2H),3.46(s,4H),3.36(s,3H),3.20(d,J＝17.6Hz,1H),1.28(d,J＝45.5Hz,3H),1.13(s,1H),1.03(s,1H),0.95–0.89(m,1H),0.87–0.80(m,1H).13C NMRδ176.74,169.42,166.09,166.07,161.64,156.83,155.17,151.28,150.95,148.86,146.23,145.42,145.15,140.01,139.94,136.79,134.56,131.33,127.88,123.12,111.03,108.37,107.18,107.14,106.90,65.48,64.18,64.14,64.07,62.44,55.27,52.66,50.95,41.08,30.47,19.10,13.93,9.45.HR MS calcd forC38H38FN5O11,[M+Na]+:782.2444,found:782.2427.
TM2a:黄色固体,m.p.:236.3-237.1℃.1H NMR(600MHz,DMSO-d6)δ14.48(s,1H),10.69(s,1H),10.54(s,1H),8.84(d,J＝3.1Hz,2H),8.82(s,1H),7.90(d,J＝2.5Hz,2H),7.73(d,J＝8.6Hz,1H),7.33(s,1H),7.08(d,J＝8.3Hz,1H),5.01(s,2H),4.34(q,J＝6.9Hz,2H),3.74(s,2H),3.42(s,8H),3.32(s,3H),1.32(t,J＝6.9Hz,3H),1.20(d,J＝5.7Hz,2H),1.00(s,1H),0.87(dd,J＝44.5,6.3Hz,1H).13C NMRδ176.59,169.15,166.08,165.54,164.89,161.81,156.91,155.25,153.11,151.28,145.14,143.85,143.76,138.31,136.80,131.25,128.61,127.96,123.12,120.31,111.11,110.98,108.41,108.18,106.86,65.48,64.14,61.58,55.27,51.63,51.08,46.36,41.98,31.38,30.47,14.45,11.29.HR MScalcd for C37H35ClFN5O10,[M+Na]+:786.1949,found:786.1936.
TM2b:黄色固体,m.p.:201.6-201.3℃.1H NMR(600MHz,DMSO-d6)δ15.25(s,1H),10.70(s,1H),10.56(s,1H),8.95(s,1H),8.86(d,J＝5.3Hz,2H),7.91(d,J＝5.7Hz,2H),7.76(d,J＝8.7Hz,1H),7.35(s,1H),7.19(d,J＝6.2Hz,1H),7.09(d,J＝8.6Hz,1H),5.02(s,2H),4.59(dd,J＝13.7,6.7Hz,1H),4.34(q,J＝7.0Hz,2H),3.89–3.64(m,4H),3.35(s,8H),2.92(dd,J＝14.6,8.2Hz,1H),1.42(t,J＝7.0Hz,3H),1.33(t,J＝7.0Hz,3H).13C NMRδ176.74,169.39,166.07,164.88,162.78,161.62,156.98,155.33,151.31,150.76,146.41,145.45,145.17,139.75,139.67,136.80,134.48,131.35,131.04,123.13,121.38,121.32,111.00,108.36,107.01,64.15,63.22,52.68,51.00,41.28,36.59,36.24,31.24,30.45,25.78,14.52.HR MS calcd for C36H36FN5O10,[M+Na]+:740.2338,found:740.2331.
TM2c:白色固体,m.p.:235.8-236.6℃.1H NMR(600MHz,DMSO-d6)δ15.18(s,1H),10.70(s,1H),10.56(s,1H),8.86(d,J＝4.4Hz,2H),8.66(s,1H),7.91(d,J＝5.4Hz,2H),7.75(d,J＝8.7Hz,1H),7.57(d,J＝7.1Hz,1H),7.35(s,1H),7.09(d,J＝8.4Hz,1H),5.01(s,2H),4.34(q,J＝6.9Hz,2H),3.80(d,J＝20.1Hz,4H),3.37(s,13H),1.33(t,J＝6.9Hz,3H).13C NMRδ176.74,169.42,166.11,166.07,164.89,163.68,161.63,155.16,151.27,150.94,148.86,146.23,145.42,145.13,142.99,140.01,136.79,134.55,131.33,127.92,123.13,111.02,108.36,107.16,106.98,106.89,65.48,64.17,64.13,64.07,62.43,55.27,52.67,41.09,30.46,19.09,13.93,9.44.HR MS calcd for C37H36FN5O10,[M+Na]+:752.2338,found:752.2333.
TM2d:黄色固体,m.p.:212.1-213.0℃.1H NMR(600MHz,DMSO-d6)δ15.09(s,1H),10.68(s,1H),9.95(s,1H),8.65(s,1H),8.01(d,J＝13.0Hz,2H),7.79(t,J＝6.0Hz,2H),7.54(t,J＝8.1Hz,2H),7.15(s,1H),6.80(dd,J＝16.6,10.5Hz,4H),6.41(d,J＝7.2Hz,1H),5.69(d,J＝10.8Hz,1H),4.34(dd,J＝13.7,6.7Hz,2H),4.02(t,J＝6.3Hz,2H),3.78(t,J＝6.3Hz,2H),3.65(m,8H),1.33(t,J＝6.9Hz,3H).13C NMRδ176.75,172.19,169.78,169.26,169.14,166.18,166.12,164.90,161.78,151.28,150.75,146.38,145.38,145.13,139.74,137.66,136.80,134.98,134.46,131.29,130.99,128.50,123.14,121.36,121.30,111.27,110.99,108.43,108.10,106.99,106.85,64.13,63.21,63.17,61.61,41.26,36.57,30.44,25.75,14.45.HR MS calcd for C40H35F2N5O10,[M+H]+:784.2425,found:784.2419.
TM2e:白色固体,m.p.:215.7-216.5℃.1H NMR(600MHz,DMSO-d6)δ15.28(s,1H),10.70(s,1H),10.55(s,1H),8.97(s,1H,H-18),8.86(d,J＝3.6Hz,2H),8.08(d,J＝13.3Hz,1H),7.91(d,J＝3.5Hz,2H),7.75(d,J＝8.6Hz,1H),7.35(s,1H),5.01(s,2H),4.50(d,J＝6.6Hz,2H),4.34(q,J＝6.9Hz,2H),4.23(t,J＝6.8Hz,2H),4.02(t,J＝6.8Hz,2H),3.96–3.63(m,8H),1.40(t,J＝6.6Hz,3H),1.33(t,J＝6.8Hz,3H).13C NMRδ176.73,169.16,166.12,166.06,164.88,163.67,161.80,151.22,150.89,148.85,146.22,145.41,145.11,142.97,140.00,139.92,134.52,131.22,127.93,123.14,110.98,108.37,107.13,106.85,65.48,64.87,62.40,61.60,61.54,55.24,41.08,30.45,19.08,14.42,9.43.HR MS calcdfor C35H35FN6O10,M+Na]+:741.2291,found:741.2297.
TM2f:黄色固体,m.p.:208.0-208.8℃.1H NMR(600MHz,DMSO-d6)δ14.95(s,1H),10.70(s,1H,H-6),10.56(s,1H),8.86(d,J＝4.7Hz,2H,H-10and H-11),8.70(s,1H,H-20),7.91(d,J＝4.6Hz,2H,H-8and H-9),7.76(d,J＝8.5Hz,1H),7.35(s,1H),7.09(d,J＝8.5Hz,1H),5.01(s,2H),4.34(dd,J＝14.1,7.0Hz,2H),4.17(t,J＝6.8Hz,2H),4.02(s,3H),3.79(d,J＝6.5Hz,3H),3.39(s,3H),3.26(s,2H),3.20–3.06(m,1H),3.04–2.69(m,2H),2.16(dd,J＝29.1,8.7Hz,1H),1.78–1.91(m,3H),1.33(t,J＝7.0Hz,3H),1.26–0.94(m,4H)..13C NMRδ176.79,172.17,169.13,166.11,164.89,162.65,161.80,151.33,150.80,146.40,145.17,139.75,136.81,134.50,131.31,130.99,128.52,123.13,121.43,111.28,110.99,108.44,107.88,107.05,106.86,64.16,63.23,63.19,62.47,61.58,51.00,50.01,43.18,41.28,34.44,30.45,30.30,25.78,14.48,9.26.HR MS calcd forC40H42FN5O11,M+H]+:788.2938,found:788.2953.
TM2g:白色固体,m.p.:223.9-224.8℃.1H NMR(600MHz,DMSO-d6)δ14.88(s,1H),10.71(s,1H),10.57(s,1H),8.92(s,1H),8.85(d,J＝4.6Hz,2H),7.91(d,J＝4.6Hz,2H),7.87(d,J＝11.6Hz,1H),7.75(d,J＝8.7Hz,1H),7.34(s,1H),5.74(t,J＝18.2Hz,7H),5.01(s,2H,H-7),4.58(s,2H,H-12),4.34(q,J＝13.9,6.9Hz,2H),4.02(t,J＝6.9Hz,4H),1.45(t,J＝6.6Hz,3H),1.33(t,J＝7.0Hz,6H).13C NMRδ176.74,172.20,169.42,166.12,166.08,164.89,163.68,161.63,155.14,151.28,150.95,148.88,146.23,145.43,145.13,142.97,139.94,136.77,134.55,131.34,123.13,111.00,108.34,107.13,106.86,65.49,64.17,64.08,62.42,55.28,52.68,51.00,41.09,30.46,19.10,13.94,9.44.HR MS calcdfor C37H37F2N5O10,[M+H]+:750.2581,found:750.2578.
TM2h:黄色固体,m.p.:233.2-234.0℃.1H NMR(600MHz,DMSO-d6)δ14.92(s,1H),10.71(s,1H),10.57(s,1H),8.85(d,J＝5.6Hz,2H),8.71(s,1H),7.91(d,J＝5.6Hz,2H),7.75(d,J＝9.1Hz,2H),7.35(s,1H),5.74(s,4H),5.01(s,2H),4.34(dd,J＝14.1,7.0Hz,2H),4.16(s,1H),3.72(s,3H,),3.35(d,J＝12.1Hz,7H),1.33(t,J＝7.1Hz,6H,),1.08(m,4H).13C NMRδ176.72,172.15,169.16,166.08,166.05,163.67,161.82,156.82,151.26,150.91,148.85,146.23,145.42,145.14,143.00,140.00,139.92,134.53,131.23,127.87,123.12,111.24,110.98,108.37,106.85,65.47,64.17,64.05,62.44,61.58,61.53,55.26,50.97,41.08,30.47,19.09,14.43,13.92,9.44.HR MS calcd for C39H40FN5O11,[M+H]+:774.2781,found:774.2780.
2目标分子TM1/TM2的抗人致病菌活性测试
2.1抗结核分枝杆菌活性
耻垢分枝杆菌是研究结核分枝杆菌和其它致病性分枝杆菌的实验模型。本发明测定了目标分子TM1/TM2对耻垢分枝杆菌Mycolicibacterium smegmatis(strain ATCC700084/mc(2)155)的最小抑菌浓度(MIC)。测试结果见表9。
表9目标分子TM1/TM2的抗耻垢分支杆菌活性测试结果
由表9可知，对测试的野生型耻垢分枝杆菌，8种FQs药物的MIC为0.0011-0.024μmol/mL，16个目标分子中有7个的MIC≤0.0054μmol/mL，显示很强的抑菌活性；其中，TM1f、TM1h和TM2h的MIC(约0.0051μmol/mL)和阳性对照药物NOR、SAR、ENX(0.0051-0.0061μmol/mL)相当；TM2b的抑菌活性(0.0043μmol/mL)是CIP(0.024μmol/mL)的5.6倍；TM1a(0.0013μmol/mL)的抑菌活性与CLX(0.0011μmol/mL)相当，是SAR(0.0051μmol/mL)的4倍、CIP(0.0236μmol/mL)的18倍；TM2a(0.00063μmol/mL)显示了最强活性，是CLX的1.7倍，是NOR、SAR、ENX的8.1-9.7倍，是CIP的37倍。上述结果表明，PAS、INA与FQ杂合，可以得到对耻垢分枝杆菌具有高抑制活性的化合物。
构效关系分析发现，PAS连接INA和CLX的衍生物(TM1a/TM2a)，其活性超越所有FQs，显示最强的抗耻垢分枝杆菌活性；乙酯化衍生物TM2(0.00063-0.14μmol/mL)对耻垢分枝杆菌的抑制活性强于甲酯化衍生物TM1(0.0013-0.14μmol/mL)。
2.2抗其它致病菌活性
为了考察目标分子的抗菌谱，按照美国国家临床实验室标准化委员会(NCCLS)推荐的微量稀释法，进一步测试了目标分子TM1/TM2对金黄色葡萄球菌(Staphyloccocusaureus)ATCC25129、金黄色葡萄球菌ATCC14125、藤黄微球菌(Micrococcus luteus)、大肠杆菌(Escherichia coli)ATCC25922、鲍曼不动杆菌(Acinetobacter baumannii)ATCC19606、沙门氏菌(Salmonella Enteritidis)ATCC13076、铜绿假单胞菌(Pseudomonasaeruginosa)ATCC27853的MIC。测试结果见表10。
表10目标分子TM1/TM2抗其它致病菌的活性测试结果(MIC,μg/mL)
注：*列中部分MIC值的单位为(μg/mL)/(μmol/mL)。
由表10可知，总体而言，目标分子TM1/TM2的抑菌活性都强于母核PAS和中间体IM3a/IM3b；PAS甲酯的抑菌活性大于PAS乙酯。
对大肠杆菌，目标分子的抑制活性整体弱于FQs但强于PAS，其中11个分子的MIC为8-64μg/mL，2个分子的MIC为16μg/mL，TM1a的MIC低至8μg/mL；总体而言，抑制活性TM1>TM2。
对沙门氏菌，总体而言，抑制活性TM1>TM2；6个目标分子的MIC≤32μg/mL，强于阳性对照药物NOR(64μg/mL)和PAS(>256μg/mL)；尤其是TM1a和TM1b，其MIC分别为0.00267、0.00284μmol/mL，强于所测试的8个FQs(0.00514-0.200μmol/mL)。
对鲍曼不动杆菌，8个FQs中，5个的MIC为256μg/mL、2个的MIC为128μg/mL；16个目标分子中，13个的MIC为256μg/mL、3个的MIC为128μg/mL。总体而言，FQs和目标分子的抑制活性都较差。
对铜绿假单胞菌，8个FQs的MIC为0.0052-0.100μmol/mL；所有目标分子的抑制活性都强于NOR(0.100μmol/mL)；TM1c、TM2d、TM2h的MIC值为8μg/mL，强于BAL；TM1h、TM2a的MIC低至4μg/mL，抑制活性相当于或强于所测试FQs；TM1a和TM1b的MIC低至2μg/mL，抑制活性强于所测试FQs。
对藤黄微球菌，8个FQs的抑制活性差别很大，MIC为0.00109-0.802μmol/mL；16个目标分子的MIC为0.00262-0.0870μmol/mL，抑制活性差别相对较小；带有CLX结构单元的TM1a和TM2a，MIC分别达到了0.00267、0.00262μmol/mL，抑制活性是NOR(0.802μmol/mL)的300倍、GAT(0.00536μmol/mL)的2倍。
对金黄色葡萄球菌ATCC 25129，目标分子整体活性弱于FQs，MIC为2-64μg/mL，其中12个目标分子的MIC≤16μg/mL。值得注意的是，TM1a和TM2h的MIC低至0.00267和0.00258μmol/mL,抑制活性是NOR(0.100μmol/mL)的38倍、GAT(0.00536μmol/mL)的2倍。对金黄色葡萄球菌ATCC 14125，8个FQs的MIC为2-4μg/mL，16个目标分子的MIC为0.125-32μg/mL，整体活性TM1>TM2；其中6个目标分子的MIC在0.000167-0.00284μmol/mL，强于所有FQs；特别地，TM1a和TM1h的MIC分别低至0.000167和0.000329μmol/mL，远远强于所有FQs(0.00536-0.0125μmol/mL)，值得后续深入研究。
3目标分子TM1a/TM2a的溶血性测试
溶血是指红细胞(RBC)破裂溶解现象。为了考察高活性目标分子TM1a/TM2a的安全性，对其进行了溶血性测试。将从健康人的新鲜血液中分离出的人红细胞用生理盐水重悬得到红细胞悬液，与不同浓度的待测化合物于37℃孵育4小时后，离心，取上清液测定吸光度，计算溶血率，以生理盐水作为阴性对照，0.1％Triton X-100的生理盐水溶液作为阳性对照。结果见图3。
由图3可知，TM1a/TM2a的溶血率随着化合物浓度的升高而升高，在1-64μg/mL的测试浓度下，TM1a的溶血率为1.32％-14.40％，TM2a的溶血率为0.0015％-8.20％；当测试浓度分别为8μg/mL及32μg/mL时，TM1a和TM2a的溶血率分别为3.73％和3.19％，溶血率均低于5％，按照国际标准，TM1a和TM2a在对应浓度下具有相对安全性；在相同浓度下，TM2a的溶血率低于TM1a，亦即PAS乙酯衍生物的溶血率低于PAS甲酯衍生物，这可能与PAS羧基酯化的烷基链越长其脂溶性越大有关。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。

Claims (6)

1.式I所示的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐：
式I中，R为甲基或乙基；
X为环丙基、乙基或4-卤代苯基；
Y为---表示与羰基的连接端；/>表示与的连接端；
Z为N或C-R1；R1为氢、卤素或甲氧基。
2.如权利要求1所述的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐，其特征在于：X为环丙基、乙基或4-氟代苯基；R1为氢、氟、氯或甲氧基。
3.以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐，其特征在于：以对氨基水杨酸为母核的三分子缀合物为以下化合物中的任一种：
4.如权利要求3所述的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐，其特征在于：以对氨基水杨酸为母核的三分子缀合物为以下化合物中的任一种：TM1a、TM1b、TM1f、TM1h、TM2a、TM2b、TM2c、TM2h。
5.权利要求1所述的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐的制备方法，其特征在于，包括以下步骤：
a.将对氨基水杨酸即PAS与醇ROH在浓硫酸催化下加热反应，制得中间体IM1；
b.将中间体IM1和氯乙酰氯在碳酸氢钠存在下、于二氯甲烷中冰浴搅拌反应，制得中间体IM2；
c.将中间体IM2和异烟酸即INA在三乙胺存在下、于二甲基亚砜中60℃油浴搅拌反应，制得中间体IM3；
d.将氟喹诺酮即FQs和3-氯丙酰氯在碳酸氢钠存在下、于二氯甲烷中冰浴搅拌反应，制得中间体IM4；
e.将中间体IM3和IM4在碳酸钾、催化剂NaI存在下、于N,N-二甲基甲酰胺中60℃油浴搅拌反应，即制得式I所述的以对氨基水杨酸为母核的三分子缀合物；
醇ROH、中间体IM1、IM2和IM3中，R都具有权利要求1所述式I中的定义；
FQs和中间体IM4中，X、Y和Z都具有权利要求1所述式I中的定义。
6.权利要求1至4任一项所述的以对氨基水杨酸为母核的三分子缀合物或其药学上可接受的盐在制备抗细菌药物中的应用，所述抗细菌药物是抗结核分枝杆菌、金黄色葡萄球菌、藤黄微球菌、大肠杆菌、鲍曼不动杆菌、沙门氏菌和铜绿假单胞菌中一种或多种的药物。
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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2005058888A2 (en) * 2003-12-18 2005-06-30 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
CN112159355A (zh) * 2020-09-25 2021-01-01 西南大学 对氨基水杨酸氟喹诺酮类衍生物及其中间体、制备方法和应用
CN112159354A (zh) * 2020-09-25 2021-01-01 西南大学 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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058888A2 (en) * 2003-12-18 2005-06-30 Morphochem Aktiengesellschaft für kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
CN112159355A (zh) * 2020-09-25 2021-01-01 西南大学 对氨基水杨酸氟喹诺酮类衍生物及其中间体、制备方法和应用
CN112159354A (zh) * 2020-09-25 2021-01-01 西南大学 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

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