CN117924324A - 一种苦参碱d环开环衍生物及其制备方法和应用 - Google Patents
一种苦参碱d环开环衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种苦参碱D环开环衍生物及其制备方法和应用，属于化学合成技术领域。所述苦参碱D环开环衍生物是以苦参酸甲酯(或苦参碱、苦参酸)、2‑溴‑苯乙酮类似物与2‑氨基噻唑‑4‑甲酸乙酯为原料合成制得，引入的活性结构噻唑杂环增强了苦参碱的抗菌活性，为进一步开发新型抗菌药物提供了依据，值得进一步研究。
Description
技术领域
本发明属于化学合成技术领域，具体涉及一种苦参碱D环开环衍生物及其制备方法和应用。
背景技术
苦参碱是从中药苦参中分离得到的一种天然生物碱，具有广谱的药理活性，如抗癌、抗炎、抗病毒、杀虫、抗菌和心肌保护作用等。苦参碱药理研究报道主要集中在抗肿瘤等方面，但对苦参碱的抗菌研究报道较少。由于大多临床抑菌药物只具有一个作用靶点，而苦参碱作为天然生物碱，发挥药理作用是多途径多系统的，但苦参碱本身活性不高。因此如何制备得到一种具有广谱抑菌活性的苦参碱衍生物成为本领域技术人员亟待解决的技术难题。
发明内容
本发明的目的在于提供一种苦参碱D环开环衍生物及其制备方法和应用。本发明以苦参酸甲酯(或苦参碱、苦参酸)、2-溴-苯乙酮类似物与2-氨基噻唑-4-甲酸乙酯为原料合成了一系列苦参碱D环开环衍生物，引入的活性结构噻唑杂环增强了苦参碱衍生物的抗菌活性，为进一步开发新型抗菌药物提供了依据，值得进一步研究。
为实现上述目的，本发明提供了如下技术方案：
本发明技术方案之一：提供一种苦参碱D环开环衍生物，结构式如式(1)所示：
式(1)中：R为下列结构之一：
本发明技术方案之二：提供一种上述苦参碱D环开环衍生物的合成方法，包括以下步骤：
将2-溴-苯乙酮类似物与2-氨基噻唑-4-甲酸乙酯反应制备中间体(1)，中间体(1)进行水解获得中间体(2)；将苦参酸甲酯、所述中间体(2)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(PYBOP)和N,N-二异丙基乙胺(DIPEA)共同反应，制得所述苦参碱D环开环衍生物；
所述2-溴-苯乙酮类似物的结构式如下：
上式中R的结构为下列结构中的一种：
所述中间体(1)的结构式如下：
所述中间体(2)的结构式如下：
所述苦参酸甲酯的结构式如下：
优选地，所述2-溴-苯乙酮类似物与2-氨基噻唑-4-甲酸乙酯经常规的加热回流即可制得中间体(1)。
优选地，所述苦参酸甲酯的制备步骤包括：将苦参碱与氢氧化钠反应制备苦参酸钠，再将苦参酸钠甲酯化，制得苦参酸甲酯。
更优选地，所述苦参碱与氢氧化钠的反应温度为120℃，时间为10～14h。
更优选地，所述苦参酸钠甲酯化的具体步骤包括：将溶有苦参酸钠的溶液加入到甲醇与二氯亚砜的反应液中，60℃反应3～5h，即得苦参酸甲酯。
本发明技术方案之三：提供一种上述苦参碱D环开环衍生物在制备抗菌药物中的应用。
优选地，所述抗菌药物包括抗痤疮丙酸杆菌药物。
本发明的有益技术效果如下：
本发明提供了一种抗菌活性强于苦参碱的苦参碱D环开环衍生物。该化合物以苦参酸甲酯(或苦参碱、苦参酸)、2-溴-苯乙酮类似物与2-氨基噻唑-4-甲酸乙酯为原料合成了一系列苦参碱D环开环衍生物，引入的活性结构噻唑杂环增强了苦参碱的抗菌活性，为进一步开发新型抗菌药物提供了依据，值得进一步研究。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。
另外，对于本发明中的数值范围，应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值，以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等，均为开放性的用语，即意指包含但不限于。
本发明实施例中所用的合成思路如下：
实施例1
化合物Z1的合成：
(1)称取1.72g(10mmol)的2-氨基噻唑-4-甲酸乙酯和2.17g(11mmol)的2-溴苯乙酮于100ml圆底烧瓶，丙酮作溶剂，回流24h，反应结束后，浓缩反应液，EA:PE＝1:3柱层析得到Z1的中间体Ⅵ1.90g，产率70％，在碱性条件下水解得到中间体Ⅶ1.62g，产率95％。
(2)称取0.488g(2mmol)Z1的中间体Ⅶ溶于干燥二氯甲烷中，在氮气氛围下0℃搅拌5分钟，加入1.2当量PYBOP，6当量DIPEA，搅拌5分钟后加入0.56g(2mmol)苦参酸甲酯固体(由苦参碱按常规方式合成获得)，0℃搅拌30分钟后置于40℃水浴锅反应8-10h。待反应结束后，浓缩反应液，加水，用二氯甲烷萃取，有机相用无水硫酸钠干燥。柱层析得到目标苦参碱衍生物Z10.678g，产率67％，油状物。
化合物Z1的核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.90(s,1H),7.85-7.83(m,2H),7.40(s,1H),7.38(d,J＝7.8Hz,2H),7.06(s,1H),4.25(s,1H),3.87(d,J＝11.0Hz,1H),3.64(s,3H),3.48(s,1H),2.70(dd,J＝44.7,11.3Hz,2H),2.35(q,J＝7.6Hz,2H),2.07-1.96(m,3H),1.86-1.75(m,5H),1.69-1.60(m,4H),1.41-1.27(m,5H).13CNMR(151MHz,CDCl3)δ173.82,160.99,148.71,147.73,134.10,128.66,127.38,126.57,125.22,109.23,62.60,56.69,56.48,54.74,51.60,39.90,35.46,33.57,31.64,29.70,28.85,28.44,21.89,21.08,20.84.HRMS(ESI)calcd for C28H34N4O3S[M+H+]，507.6352，found,507.2430.
实施例2
化合物Z2-Z20的合成：
合成方法参考Z1的合成方法(原料的摩尔量相同)，区别在于化合物Ⅴ的R1取代基不同，化合物Z2-Z20的表征数据如下。
Z2：0.887g，产率76％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.91(s,1H),7.74-7.68(m,2H),7.53-7.47(m,2H),7.08(s,1H),4.25(s,1H),3.87(s,1H),3.64(s,3H),3.50(d,J＝17.8Hz,1H),2.83-2.56(m,2H),2.35(q,J＝10.6,7.4Hz,2H),2.02(d,J＝39.4Hz,3H),1.91-1.72(m,5H),1.72-1.59(m,4H),1.43-1.26(m,5H).13C NMR(151MHz,CDCl3)δ173.79,162.51,160.81,148.85,146.57,133.14,131.72,126.75,121.05,113.73,109.48,62.50,56.64,56.44,54.65,51.58,39.89,36.46,35.30,33.51,31.41,28.72,28.44,21.86,21.07,20.81.HRMS(ESI)calcdfor C28H33BrN4O3S[M+H+]，585.1457，found，585.1526.
Z3：0.841g，产率72％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.02(t,J＝1.8Hz,1H),7.92(s,1H),7.75(dt,J＝7.7,1.3Hz,1H),7.38(ddd,J＝7.9,2.0,1.0Hz,1H),7.24(t,J＝7.9Hz,1H),7.08(s,1H),4.25(s,1H),3.88(d,J＝30.4Hz,1H),3.65(s,3H),3.48(s,1H),2.69(dd,J＝44.9,11.1Hz,2H),2.35(q,J＝8.0,7.5Hz,2H),2.03(d,J＝3.4Hz,3H),1.86-1.76(m,5H),1.70-1.56(m,4H),1.44-1.27(m,5H).13C NMR(151MHz,CDCl3)δ
173.83,160.80,148.89,146.20,136.22,130.21,130.18,128.23,126.57,123.68,122.90,114.00,109.82,62.56,56.68,56.47,54.83,51.65,39.90,35.50,33.54,31.62,29.70,28.82,28.45,21.88,21.10,20.86.HRMS(ESI)calcd for C28H33BrN4O3S[M+H+]，585.1457，found，585.1825.
Z4：0.67g，产率62％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.90(s,1H),7.77(d,J＝8.5Hz,2H),7.35(d,J＝8.5Hz,2H),7.08(s,1H),4.26(s,1H),3.87(s,1H),3.65(s,3H),3.51(d,J＝18.4Hz,1H),2.70(dd,J＝44.1,11.2Hz,2H),2.36(q,J＝8.2Hz,2H),2.01(d,J＝33.2Hz,3H),1.89-1.75(m,5H),1.70-1.57(m,4H),1.44-1.23(m,5H).13C NMR(151MHz,CDCl3)δ173.84,171.27,161.12,148.88,146.61,133.01,132.59,128.84,126.49,115.85,109.46,60.42,56.66,56.47,54.73,51.61,33.54,31.64,29.70,29.65,29.37,28.40,22.70,21.87,21.06,20.82.HRMS(ESI)calcd for C28H33ClN4O3S[M+H+]，541.1962，found，541.2030.
Z5：0.677g，产率59％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.96(d,J＝2.0Hz,1H),7.94(s,1H),7.65(dd,J＝8.3,2.1Hz,1H),7.43(d,J＝8.4Hz,1H),7.10(s,1H),4.25(s,1H),3.84(s,1H),3.65(s,3H),3.51(d,J＝21.1Hz,1H),2.68(dd,J＝44.9,11.1Hz,2H),2.34(q,J＝15.8,8.3,7.0Hz,2H),2.02(d,J＝3.4Hz,3H),1.89-1.71(m,5H),1.73-1.55(m,4H),1.42-1.24(m,5H).13C NMR(151MHz,CDCl3)δ173.85,161.17,149.02,145.44,135.20,134.66,132.81,130.90,130.58,127.03,124.73,114.35,109.98,62.53,56.67,56.46,54.84,51.64,39.92,35.35,33.51,31.65,29.70,28.90,28.45,21.87,21.10,20.86.HRMS(ESI)calcd forC28H32Cl2N4O3S[M+H+]，575.1572，found，575.1655.
Z6：0.838g，产率80％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.84(s,1H),7.79(dd,J＝8.7,5.5Hz,2H),7.08-7.05(m,2H),7.04(d,J＝2.2Hz,1H),4.24(s,1H),3.85(s,1H),3.63(s,3H),3.46(s,1H),2.68(dd,J＝44.6,11.2Hz,2H),2.34(q,2H),1.99(d,J＝30.5Hz,3H),1.85-1.72(m,5H),1.70-1.57(m,4H),1.43-1.25(m,5H).13C NMR(151MHz,CDCl3)δ173.80,163.09,161.46,160.90,148.73,146.84,130.37,126.88,126.82,115.61,115.46,113.52,108.94,62.54,56.67,56.46,54.70,51.57,39.90,35.38,33.54,31.61,29.69,28.72,28.44,21.87,21.08,20.83.HRMS(ESI)calcd for C28H33FN4O3S[M+H+]，525.2257，found，525.2325.
Z7：0.856g，产率79％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.16(d,J＝6.6Hz,1H),7.92(d,J＝4.0Hz,1H),7.02(s,1H),6.95(d,J＝2.5Hz,1H),6.86(d,J＝2.5Hz,1H),4.24(s,1H),3.89(s,1H),3.64(s,3H),3.44(s,1H),2.71(dd,J＝44.0,11.1Hz,2H),2.35(q,J＝6.8Hz,2H),1.98(d,J＝32.9Hz,3H),1.85-1.72(m,5H),1.71-1.58(m,4H),1.45-1.25(m,5H).13C NMR(151MHz,CDCl3)δ173.74,160.86,160.37,158.63,148.35,140.38,129.04,126.64,118.32,113.28,112.72,111.64,104.01,62.54,56.51,56.35,54.96,51.57,40.01,35.59,33.58,31.93,29.87,28.99,28.59,21.89,21.05,
20.75.HRMS(ESI)calcd for C28H32F2N4O3S[M+H+]，543.2163，found，543.2531.
Z8：0.712g，产率62％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.99(s,1H),7.94(d,J＝8.1Hz,2H),7.63(d,J＝8.2Hz,2H),7.10(s,1H),4.26(s,1H),3.87(s,1H),3.64(s,3H),3.51(d,J＝14.7Hz,1H),2.68(dd,J＝45.5,11.2Hz,2H),2.33(q,J＝15.9,8.5Hz,2H),2.03(d,J＝3.4Hz,3H),1.86-1.76(m,5H),1.70-1.58(m,4H),1.43-1.25(m,5H).13C NMR(151MHz,CDCl3)δ173.83,160.77,149.11,146.22,137.58,128.95,126.49,125.63,125.26,123.42,114.24,110.40,62.51,56.66,56.46,54.75,51.60,39.93,35.45,33.51,31.63,29.69,28.91,28.47,21.87,21.09,20.83.HRMS(ESI)calcd for C29H33F3N4O3S[M+H+]，575.2225，found，575.2314.
Z9：0.743g，产率63％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.90(s,1H),7.85(d,J＝8.7Hz,2H),7.22(d,J＝8.2Hz,2H),7.08(s,1H),4.25(s,1H),3.86(s,1H),3.64(s,3H),3.48(d,J＝12.9Hz,1H),2.68(dd,J＝44.9,11.2Hz,2H),2.34(q,2H),2.00(d,J＝29.1Hz,3H),1.88-1.74(m,5H),1.69-1.58(m,4H),1.44-1.21(m,5H).13C NMR(151MHz,CDCl3)δ173.83,160.85,148.90,148.41,146.41,132.95,126.51,121.37,121.19,119.67,113.73,109.53,62.53,56.67,56.46,54.64,51.58,39.92,35.52,33.52,31.47,29.69,28.74,28.45,21.86,21.08,20.82.HRMS(ESI)calcd for C29H33F3N4O4S[M+H+]，591.2175，found，591.2572.
Z10：0.695g，产率55％，淡黄色固体，熔点：66.3℃～68.4℃；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.91(s,1H),7.70(d,J＝8.5Hz,2H),7.58(d,J＝8.4Hz,2H),7.07(s,1H),4.24(s,1H),3.88(d,J＝30.3Hz,1H),3.64(s,3H),3.50(d,J＝21.8Hz,1H),2.68(dd,J＝44.5,11.3Hz,2H),2.34(q,2H),2.03(d,3H),1.87-1.75(m,5H),1.70-1.57(m,4H),1.42-1.24(m,5H).13C NMR(151MHz,CDCl3)δ173.46,160.85,148.86,146.26,137.70,133.70,126.99,126.52,113.96,110.02,92.55,62.55,56.67,56.47,54.69,51.61,39.90,35.41,33.54,31.65,29.70,28.89,28.45,21.87,21.09,20.84.HRMS(ESI)calcd for C28H33IN4O3S[M+H+]，633.1318，found，633.1742.
Z11：0.614g，产率59％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.85(s,1H),7.72(d,J＝8.2Hz,2H),7.19(d,J＝7.9Hz,2H),7.04(s,1H),4.24(s,1H),3.86(s,1H),3.64(s,3H),3.47(s,1H),2.70(dd,J＝44.8,11.1Hz,2H),2.35(s,3H),2.34(q,2H),2.01(d,J＝25.2Hz,3H),1.85-1.71(m,5H),1.70-1.54(m,4H),1.43-1.22(m,5H).13C NMR(151MHz,CDCl3)δ173.80,161.40,148.57,147.85,137.11,131.32,129.36,126.24,125.13,113.52,108.79,62.62,56.68,56.48,54.78,51.59,39.87,35.45,33.58,31.55,29.70,28.68,28.42,21.88,21.25,21.07,20.83.HRMS(ESI)calcd for C29H36N4O3S[M+H+]，521.2508，found，521.2577.
Z12：0.675g，产率63％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.80(s,1H),7.76(d,J＝8.7Hz,2H),7.03(s,1H),6.93(d,J＝8.8Hz,2H),4.23(d,J＝5.5Hz,1H),3.87(s,1H),3.83(s,3H),3.64(s,3H),3.47(s,1H),2.70(dd,J＝43.4,11.2Hz,2H),2.35(q,J＝7.3Hz,2H),2.01(d,J＝23.3Hz,3H),1.86-1.74(m,5H),1.71-1.59(m,4H),1.43-1.28(m,5H).13C NMR(151MHz,CDCl3)δ173.83,161.51,159.11,149.14,147.65,126.93,126.58,126.48,114.09,113.37,108.23,62.64,56.68,56.48,55.31,54.89,51.59,39.85,35.59,33.58,31.35,29.70,28.76,28.38,21.88,21.05,20.81.HRMS(ESI)calcd for C29H36N4O4S[M+H+]，537.2457，found，537.2527.
Z13：0.60g，产率53％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.82(s,1H),7.42(d,J＝2.0Hz,1H),7.35(dd,J＝8.3,2.0Hz,1H),7.05(s,1H),6.88(d,J＝8.3Hz,1H),4.22(d,J＝8.7Hz,1H),3.95(s,3H),3.89(s,3H),3.83(s,1H),3.63(s,3H),3.49(d,J＝15.4Hz,1H),2.70(dd,J＝41.6,11.2Hz,2H),2.34(q,J＝7.1Hz,2H),2.03(d,J＝3.4Hz,3H),1.88-1.75(m,5H),1.71-1.57(m,4H),1.44-1.25(m,5H).13C NMR(151MHz,CDCl3)δ173.80,161.04,149.16,148.55,148.51,147.70,127.29,126.50,117.54,113.59,111.36,108.59,108.49,62.65,56.69,56.49,55.98,55.96,54.97,51.58,39.84,35.69,33.60,31.35,29.65,28.90,28.35,21.90,21.08,20.87.HRMS(ESI)calcd for C30H38N4O5S[M+H+]，567.2563，found，567.2957.
Z14：0.566g，产率50％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.11(s,1H),7.83(d,J＝3.1Hz,1H),7.00(s,1H),6.88(d,J＝8.9Hz,1H),6.79(dd,J＝8.9,3.2Hz,1H),4.24(d,J＝7.0Hz,1H),3.90(s,1H),3.88(s,3H),3.85(s,3H),3.63(s,3H),3.42(s,1H),2.71(dd,J＝45.3,11.0Hz,2H),2.36(q,J＝7.1,3.0Hz,2H),2.00(d,J＝18.6Hz,3H),1.85-1.73(m,5H),1.72-1.58(m,4H),1.43-1.23(m,5H).13C NMR(151MHz,CDCl3)δ173.75,161.16,153.90,150.63,147.64,143.11,126.75,123.40,114.16,113.67,113.00,112.27,112.24,62.64,56.55,56.37,55.94,55.91,54.84,51.56,39.95,35.52,33.64,31.65,29.70,28.87,28.46,21.94,21.02,20.76.HRMS(ESI)calcd for C30H38N4O5S[M+H+]，567.2563，found，567.2962.
Z15：0.85g，产率73％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ7.95(s,1H),7.94-7.89(m,2H),7.65-7.64(m,2H),7.63(q,J＝1.5,1.0Hz,2H),7.46-7.41(m,2H),7.36-7.31(m,1H),7.07(s,1H),4.26(s,1H),3.89(s,1H),3.66(s,3H),3.52(d,J＝19.2Hz,1H),2.72(dd,J＝44.7,11.1Hz,2H),2.37(q,J＝7.8Hz,2H),2.03(d,J＝28.1Hz,3H),1.88-1.78(m,5H),1.70-1.60(m,4H),1.44-1.27(m,5H).13C NMR(151MHz,CDCl3)δ
173.49,161.02,148.81,147.43,140.84,140.07,133.15,128.77,127.37,127.22,126.95,126.57,125.60,113.73,109.34,62.65,56.69,56.50,54.63,51.62,39.88,36.20,33.99,31.51,29.71,28.85,28.40,21.90,21.06,20.82.HRMS(ESI)calcdfor C34H38N4O3S[M+H+]，583.2665，found，583.2732.
Z16：0.856g，产率77％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.40-8.34(m,1H),8.03(s,1H),7.91(dd,J＝8.5,1.7Hz,1H),7.88(dd,J＝8.1,1.3Hz,1H),7.85(d,J＝8.6Hz,1H),7.81(dd,J＝8.0,1.4Hz,1H),7.46(ddd,J＝8.1,6.8,1.5Hz,1H),7.43(ddd,J＝8.1,6.8,1.5Hz,1H),7.09(s,1H),4.26(s,1H),3.89(s,1H),3.65(s,3H),3.52(d,J＝9.7Hz,1H),2.73(dd,J＝46.0,11.2Hz,2H),2.37(q,J＝8.0,7.5Hz,2H),2.05(d,J＝3.3Hz,3H),1.86-1.76(m,5H),1.73-1.61(m,4H),1.44-1.27(m,5H).13C NMR(151MHz,CDCl3)δ173.84,161.25,148.98,147.76,133.77,132.92,131.40,128.27,128.24,127.68,126.59,126.23,125.71,123.73,123.63,113.87,109.73,62.46,56.69,56.50,54.76,51.62,39.90,35.97,33.61,31.64,29.71,28.84,28.41,21.90,21.08,20.85.HRMS(ESI)calcd for C32H36N4O3S[M+H+]，557.2508，found，557.2576.
Z17：0.85g，产率80％，白色蓬松状固体，熔点89.2℃～91.7℃；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.02(s,1H),7.93(d,J＝8.4Hz,2H),7.69-
7.59(m,2H),7.12(s,1H),4.27(s,1H),3.86(s,1H),3.64(s,3H),3.51(d,J＝15.6Hz,1H),2.68(dd,J＝46.0,11.1Hz,2H),2.34(q,2H),2.03(d,3H),1.89-1.76(m,5H),1.72-1.59(m,4H),1.44-1.27(m,5H).13C NMR(151MHz,CDCl3)δ173.84,161.34,149.36,145.72,138.59,132.56,126.47,125.51,119.17,114.57,111.04,110.01,62.47,56.67,56.45,54.62,51.61,39.96,35.35,33.49,31.64,29.64,28.87,28.50,21.87,21.10,20.84.HRMS(ESI)calcd for C29H33N5O3S[M+H+]，532.2304，found，532.2722.
Z18：0.907g，产率69％，黄色蓬松状固体，熔点：122.6℃～125.2℃；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.31(d,J＝2.2Hz,1H),7.98(dd,J＝8.7,2.3Hz,1H),7.92(s,1H),7.46(d,J＝7.2Hz,2H),7.38(t,J＝7.6Hz,2H),7.32(t,J＝7.4Hz,1H),7.14(d,J＝8.8Hz,1H),7.09(s,1H),5.25(s,2H),4.25(s,1H),3.84(s,1H),3.64(s,3H),3.50(s,1H),2.69(dd,J＝44.7,11.1Hz,2H),2.34(q,J＝16.4,7.6Hz,2H),2.00(d,J＝41.8Hz,3H),1.85-1.77(m,5H),1.70-1.59(m,4H),1.42-1.26(m,5H).13C NMR(151MHz,CDCl3)δ173.86,160.74,150.93,149.00,145.26,140.44,135.64,130.47,128.70,128.22,127.65,127.03,126.59,122.26,115.48,114.14,109.44,71.32,62.52,56.67,56.46,54.86,51.62,39.92,35.74,33.53,31.70,29.70,28.87,28.47,21.87,21.11,20.87.HRMS(ESI)calcd forC35H39N5O6S[M+H+]，658.2621，found，658.3078.
Z19：0.904g，产率82％，黄色蓬松状固体，熔点：85.3℃～87.1℃；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.25-8.20(m,2H),8.08(s,1H),8.03-7.91(m,2H),7.14(s,1H),4.27(s,1H),3.86(s,1H),3.64(s,3H),3.50(d,J＝20.5Hz,1H),2.68(dd,J＝46.1,11.1Hz,2H),2.34(q,J＝7.3,6.7Hz,2H),1.99(d,J＝43.8Hz,3H),1.87-1.72(m,5H),1.68-1.54(m,4H),1.47-1.36(m,5H).13C NMR(151MHz,CDCl3)δ174.25,160.59,149.56,146.70,145.37,141.04,126.46,125.49,124.20,114.94,111.56,62.46,56.66,56.44,54.65,51.62,39.95,35.35,33.48,31.89,29.69,29.00,28.49,21.86,21.10,20.84.HRMS(ESI)calcd for C28H33N5O5S[M+H+]，552.2202，found，552.2294.
Z20：0.712g，产率62％，油状物；其核磁共振氢谱、核磁共振碳谱和高分辨质谱数据如下：
1H NMR(600MHz,CDCl3)δ8.22(s,1H),8.12(d,J＝8.6Hz,1H),7.42(d,J＝2.1Hz,1H),7.29(dd,J＝8.5,2.1Hz,1H),7.08(s,1H),4.23(s,1H),3.87(s,1H),3.63(s,3H),3.45(s,1H),2.70(dd,J＝39.2,11.1Hz,2H),2.34(q,J＝7.0Hz,2H),1.99(d,J＝18.7Hz,3H),1.84-1.74(m,5H),1.69-1.56(m,4H),1.44-1.31(m,5H).13C NMR(151MHz,CDCl3)δ173.73,160.78,148.01,142.75,132.99,131.40,131.07,131.02,130.01,127.27,126.66,114.01,113.63,62.60,56.60,56.41,54.78,51.58,39.89,35.60,33.58,31.60,29.97,28.82,28.45,21.89,21.04,20.81.HRMS(ESI)calcd for C28H32Cl2N4O3S[M+H+]，575.1572，found，575.1640.
化合物Z1-Z20的结构式见表1。
表120个苦参碱D环开环衍生物的结构式
考察化合物Z1-Z20的抑菌活性：
实验方法：
1、培养基的配制
1.1、Luria-Bertani(LB)培养基的配制：向100mL去离子水中加入1g胰蛋白胨、0.5g酵母提取液和1g NaCl，搅拌均匀，微热使其完全溶解，瓶口用干净的纱布和纸张覆盖，最后用橡皮筋绑紧，防止引入杂菌，将培养基放入灭菌锅121℃，20min，烘箱内烘干，待后续实验之用；
1.2、YM培养基的配制：向100mL去离子水中加入0.5g蛋白胨、1g葡萄糖、0.3g酵母浸粉和0.3g麦芽糖，搅拌均匀，微热使其完全溶解，瓶口用干净的纱布和纸张覆盖，最后用橡皮筋绑紧，防止引入杂菌，将培养基放入灭菌锅115℃，20min，烘箱内烘干，待后续实验之用；
1.3、1053培养基的配制：向100mL去离子水中加入1g蛋白胨、0.5g葡萄糖、0.3g酵母浸粉、0.1g可溶性淀粉、1g牛肉膏、0.5g氯化钠、0.3g乙酸钠和0.05g L-半胱氨酸盐酸盐，搅拌均匀，微热使其完全溶解，瓶口用干净的纱布和纸张覆盖，最后用橡皮筋绑紧，防止引入杂菌，将培养基放入灭菌锅115℃，20min，烘箱内烘干，待后续实验之用。
2、供试菌的制备
2.1、培养铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌：从冰箱内取出供试菌，在超净工作台上量取50μL菌种接种于15mL LB肉汤中，置于37℃空气浴恒温培养箱中过夜培养，隔日观察菌落生长的情况，达到稳定期测定菌种OD600值为0.5～1。
2.2、培养白色念珠菌：从冰箱内取出供试菌，在超净工作台上量取50μL菌种接种于15mLYM肉汤中，置于30℃空气浴恒温培养箱中培养24h，隔日观察菌落生长的情况，达到稳定期测定菌种OD600值为0.5～1。
2.3、培养痤疮丙酸杆菌：从冰箱内取出供试菌，在超净工作台上量取50μL菌种接种于35mL 1053肉汤中，置于37℃空气浴恒温培养箱中培养48h，隔日观察菌落生长的情况，达到稳定期测定菌种OD600值为0.5～1。
3、供试菌的低温保存(未使用完的菌种)
低温保存时用30％的甘油与目标菌液以体积比1︰1混合，装入冻存管，密封后贴上标签，置于-20℃冰箱内保存。
4、待测化合物溶液的配制
称取16mg化合物样品，用微量移液枪量取10μL DMSO溶解，再加入990μL肉汤培养基稀释。铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌(LB培养基)；白色假丝酵母菌(YM培养基)；痤疮丙酸杆菌(1053培养基)。
5、最小抑菌浓度(MIC)的测试
采用二倍稀释法测试目标化合物抑菌活性。将实验所需的各种规格枪头、96孔板、配制好的待测样品等置于超净工作台中，紫外灭菌30min，用微量移液枪在96孔板的每个孔中加入100μL肉汤，然后再在第一排孔中加入100μL已配制为16mg/mL的待测试样品，将第一排的药液混合均匀后吸取100μl测试液进入第二排孔中，以此类推，直至加入到最后一孔，在最后一孔吸出100μL弃去，之后的每排孔都重复相同的操作，最终测试液浓度为：8、4、2、1、0.5、0.25、0.125、0.0625mg/mL，每个样品重复3次试验。每孔中加入5μL培养好的菌液，将96酶标板置于37℃培养箱中孵育12h，再使用600nm波长的酶标仪测定吸光度(OD值)。不同菌种选择不同的抗生素作为阳性对照，同时，苦参碱也作为阳性对照，1％二甲基亚砜和肉汤培养基为阴性对照，实验结果见表2。
表2苦参碱D环开环衍生物的抑菌活性实验结果
表2中，大肠杆菌相应的阳性对照药为：硫酸卡那霉素(批号：91HR6RYX)；铜绿假单胞菌对照药为：头孢他啶(批号：9DDADRLX)；金黄色葡萄球菌对照药为：青霉素G钠(批号：4006206333)；痤疮丙酸杆菌对照药为：盐酸多西环素(批号：4006206333)；白色假丝酵母对照药为：氟康唑(批号：93MNRN8R)；以上标准品均购于萨恩化学技术(上海)有限公司。
从表2中可以看出，所有设计的苦参碱D环开环衍生物对大肠杆菌、铜绿假单胞菌、金黄色葡萄球菌、痤疮丙酸杆菌和白色假丝酵母菌的抑菌效果均优于苦参碱，其中化合物Z2、Z3、Z4、Z15、Z16和Z18表现出较强的抑菌活性，Z18的抑菌活性最佳，对痤疮丙酸杆菌的MIC为0.0175mg/mL，抑菌活性均优于苦参碱，并且还高于其阳性对照药物盐酸多西环素。已有报道证明苦参碱在治疗痤疮中发挥了重要的作用，说明苦参碱可能是一种潜在的痤疮缓解候选物。该研究结果为进一步开发抗痤疮丙酸杆菌新药提供有益的参考，值得进一步研究。
以上所述的实施例仅是对本发明的优选方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案做出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (7)
1.一种苦参碱D环开环衍生物，其特征在于，结构式如式(1)所示：
式(1)中：R为下列结构之一：
2.一种权利要求1所述苦参碱D环开环衍生物的合成方法，其特征在于，包括以下步骤：
将2-溴-苯乙酮类似物与2-氨基噻唑-4-甲酸乙酯反应制备中间体(1)，中间体(1)进行水解获得中间体(2)；将苦参酸甲酯、所述中间体(2)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐和N,N-二异丙基乙胺共同反应，制得所述苦参碱D环开环衍生物；
所述2-溴-苯乙酮类似物的结构式如下：
上式中R的结构为下列结构中的一种：
所述中间体(1)的结构式如下：
所述中间体(2)的结构式如下：
所述苦参酸甲酯的结构式如下：
3.根据权利要求2所述的制备方法，其特征在于，所述苦参酸甲酯的制备步骤包括：将苦参碱与氢氧化钠反应制备苦参酸钠，再将苦参酸钠甲酯化，制得苦参酸甲酯。
4.根据权利要求3所述的制备方法，其特征在于，所述苦参碱与氢氧化钠的反应温度为120℃，时间为10～14h。
5.根据权利要求3所述的制备方法，其特征在于，所述苦参酸钠甲酯化的具体步骤包括：将溶有苦参酸钠的溶液加入到甲醇与二氯亚砜的反应液中，60℃反应3～5h，即得苦参酸甲酯。
6.权利要求1所述苦参碱D环开环衍生物在制备抗菌药物中的应用。
7.权利要求1所述苦参碱D环开环衍生物在制备抗痤疮丙酸杆菌药物中的应用。
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