CN105859537B - 开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用 - Google Patents
开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用 Download PDFInfo
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Abstract
本发明公开了开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用。开环桃金娘酮类似物,其结构如式(1)所示:其中R为H、C1‑C15直链、支链或环烷基、或芳香基团。本发明的开环桃金娘酮类似物具有显著的抗Methicillin‑resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli活性,因此可以用于制备抗细菌感染类药物,尤其是在防治临床上常见的Methicillin‑resistant Staphylococcus aureus(MRSA)感染性疾病上的应用。
Description
技术领域:
本发明属于合成药物化学领域,具体涉及开环桃金娘酮类似物及其制备方法和在抗菌药物中的应用。
背景技术:
耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA),自1961年英国Jevons首次发现以来,在金黄色葡萄球菌感染中所占的比例越来越高,已经由20世纪80年代中期的1%-5%迅速增加至目前的60%-70%,而且感染程度越来越严重,已成为医院和社区感染的重要病原菌之一。当前MRSA对临床上常用的抗生素相继出现耐药性,已成为严重威胁人类健康的多重耐药性病原菌,其感染几乎遍及世界,并可在牲畜和人际间传播,感染后导致的菌血症死亡率高达50%-80%。目前,MRSA感染已与乙型肝炎、艾滋病并列为当今世界三大最难解决的感染性疾病。
MRSA具有多重耐药性,对β-内酰胺等几乎所有临床常用抗生素表现出耐药性。万古霉素(Vancomycin)曾一度被认为是治疗MRSA感染的首选抗生素,但该抗生素毒副作用大,长期大剂量使用对肾脏损害严重,容易造成耳聋,因此并不作为一线药物使用。除万古霉素外,利奈唑胺、达托霉素和替加环素等少数药物经美国FDA批准,虽然也能用于临床治疗MRSA感染,但近年来上述药物的耐药菌株在临床上不断地被发现,并且几率逐渐增加,已引起医学界的广泛关注。鉴于目前还没有十分满意的抗MRSA感染药物,因此开发新型抗MRSA感染药物显得尤为迫切,同时具有重大的科学意义、广阔的市场前景和潜在的经济价值。
Semimyrtucommulone(2)和callistenone C(3)都是从桃金娘属植物中分离出来的,它们都是由一个β-三酮和酰基间苯三酚单元经过Michael加成反应聚合而成,为桃金娘属植物中的特征成分。前人的活性实验研究表明,它们具有良好的抗菌活性(对金黄色葡萄球菌Staphylococcus aureus的MIC都为8.0μg/mL)。由于分子中的间苯三酚片段与β-三酮片段并未发生脱水而形成关环,因而具有多羟基开环的结构。由于其独特的结构特点,因而使得它们的全合成相对较为简单。基于它们前述的特点,因而本发明将以它们作为研究对象进行构效关系研究,以发现具有显著抗菌特别是抗MRSA活性的先导药物分子,具有重要的科学意义和潜在的经济价值。
发明内容:
本发明的第一个目的是提供具有显著的抑制Methicillin-resistantStaphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli生长的开环桃金娘酮类似物。
本发明的开环桃金娘酮类似物,其结构如式(1)所示:
其中R为H、或C1-C15直链、支链以及环烷基或含有苯环等结构的芳香基团。
所述的开环桃金娘酮类似物优选为式(2)中的任一化合物:
进一步优选,所述的开环桃金娘酮类似物为式(3)中的任一化合物:
本发明的第二个目的是提供一种上述开环桃金娘酮类似物的制备方法,其特征在于,其合成过程如下:
合成流程如式(4)所示:
用间苯三酚与烷基酰氯在甲磺酸或者三氯化铝的催化下,经过傅克酰基化反应得到式(4)中的前体化合物6;另一前体化合物10是通过以乙酰基间苯三酚6b作原料,在碱性条件下进行C-甲基化得到化合物7,然后化合物7再经过质子酸催化的逆Claisen缩合和Knoevenagel缩合得到;前体化合物6和化合物10(α,β-不饱和酮)在碱性条件下,发生Michael加成反应,即可得到目标产物11,其中R为H、C1-C15直链、支链以及环烷基或含有苯环等结构的芳香基团。
.本发明的上述开环桃金娘酮类似物具有非常显著的抗革兰氏阳性菌的活性,其中化合物11i-11n的抗菌活性比抗菌药“最后一道屏障”万古霉素好2-4倍。
因此,本发明的第三个目的是提供上述开环桃金娘酮类似物中的任一化合物在制备抗菌药物中的应用。
所述的抗菌药物优选为抗Methicillin-resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli细菌的药物。由于本发明的开环桃金娘酮类似物对上述细菌具有较好的抑菌活性,因此能够开发成广谱的细菌杀灭剂。
所述的抗菌药物为抗细菌感染剂或防治细菌感染药物。
本发明的第四个目的是提供提供一种抗菌药物,其特征在于,含有上述开环桃金娘酮类似物中的任一化合物作为活性成份,和药学上可以接受的载体。
所述的抗菌药物优选为抗Methicillin-resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli细菌的药物。
所述的抗菌药物为抗细菌感染剂或防治细菌感染药物。
本发明合成了一类具有显著抗Methicillin-resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli的开环桃金娘酮类似物,它们的抗菌活性比抗菌药“最后一道屏障”万古霉素好2-4倍,并提供了一种合成上述化合物的简便方法。由于本发明的开环桃金娘酮类似物具有显著的抗Methicillin-resistant Staphylococcus aureus(MRSA)、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichiacoli活性,因此可以用于制备抗细菌感染类药物,尤其是在防治临床上常见的Methicillin-resistant Staphylococcus aureus(MRSA)感染性疾病上的应用。
具体实施方式:
以下实施例是对本发明的进一步说明,而不是对本发明的限制。
实施例1:开环桃金娘酮类似物的制备方法:
本发明的开环桃金娘酮类似物的合成过程如下所示:
用间苯三酚与烷基酰氯在甲磺酸或者三氯化铝的催化下,经过傅克酰基化反应得到式(5)中的前体化合物6,其中R为H、C1-C15直链、支链以及环烷基或含有苯环等结构的芳香基团;另一前体化合物10则可以通过以乙酰基间苯三酚6b作原料,在碱性条件下进行C-甲基化,然后再经过质子酸催化的逆Claisen缩合和Knoevenagel缩合快速得到;得到的前体化合物6和化合物10(α,β-不饱和酮)后,进一步在碱性条件下,促使它们发生Michael加成反应,即可顺利得到目标产物11,其中R为H、C1-C15直链、支链以及环烷基或含有苯环等结构的芳香基团。
具体步骤如下:
化合物6b-6k的合成
(1)将间苯三酚(315mg,2.5mmol)和酰氯(3.75mmol)置于10mL干燥的圆底烧瓶中,加热升温至60-80℃。搅拌10分钟后,向反应体系中缓慢滴加甲基磺酸(25mmol,1.6mL)。继续保持在温度下搅拌反应体系30分钟,然后冷至室温。将反应混合物倾倒入25mL冰水中,并用乙酸乙酯(25mL)萃取3次,合并有机相,并分别用25mL饱和碳酸氢钠和食盐水洗涤。有机相经无水硫酸钠干燥后过滤,所得滤液在减压条件旋干。剩余的油状混合物经过快速柱层析(正己烷:乙酸乙酯=5:1)分离,得到相应的酰基间苯三酚化合物。
所述的酰氯
当R为H时,所得化合物为6a;
当R为CH3时,所得化合物为式(5)中的6b;
当R为C2H5时,所得化合物为式(5)中的6c;
当R为C3H5时,所得化合物为式(5)中的6d;
当R为iPr时,所得化合物为式(5)中的6e;
当R为C4H9时,所得化合物为式(5)中的6f;
当R为iBu时,所得化合物为式(5)中的6g;
当R为C5H11时,所得化合物为式(5)中的6h;
当R为C6H13时,所得化合物为式(5)中的6i;
当R为C7H15时,所得化合物为式(5)中的6j;
当R为C8H17时,所得化合物为式(5)中的6k;
化合物6l-6u的合成
(2)将间苯三酚(315mg,2.5mmol)和酰氯(3.75mmol)置于10mL干燥的圆底烧瓶中,加热升温至60-80℃。搅拌10分钟后,向反应体系中缓慢加入三氯化铝(12.5mmol,1.66g)。继续保持在温度下搅拌反应体系3个小时,然后冷至室温。将反应混合物倾倒入25mL冰水中,并用乙酸乙酯(25mL)萃取3次,合并有机相,并分别用25mL饱和碳酸氢钠和食盐水洗涤。有机相经无水硫酸钠干燥后过滤,所得滤液在减压条件旋干。剩余的油状混合物经过快速柱层析(正己烷:乙酸乙酯=5:1)分离,得到相应的酰基间苯三酚化合物。
所述的酰氯
当R2为C9H17时,所得化合物为式(5)中的6l;
当R2为C10H21时,所得化合物为式(5)中的6m;
当R2为C11H23时,所得化合物为式(5)中的6n;
当R2为C13H27时,所得化合物为式(5)中的6o;
当R2为C15H31时,所得化合物为式(5)中的6p;
当R2为c-C4H7时,所得化合物为式(5)中的6q;
当R2为c-C5H9时,所得化合物为式(5)中的6r;
当R2为c-C6H11时,所得化合物为式(5)中的6s;
当R2为CH2Ph时,所得化合物为式(5)中的6t;
当R2为C2H4Ph时,所得化合物为式(5)中的6u;
化合物7的合成
在冰浴条件下,将乙酰基间苯三酚(2.75g,16.5mmol)溶于60mL无水的甲醇溶液中,然后慢慢地加入甲醇钠(7.2g,133mmol)。均匀搅拌10分钟后,向反应体系中慢慢滴加碘甲烷(14.2mL,228mmol)。继续在冰浴条件下搅拌30分钟,紧接着将反应混合物置于室温下搅拌24个小时。然后加入100mL 2N的盐酸水溶液终止反应。混合物用乙酸乙酯(100mL)萃取4次,合并有机相。所得到的有机相用50mL饱和食盐水洗涤,无水硫酸钠干燥,过滤。剩余物经过快速柱层析(正己烷:乙酸乙酯=5:1)进一步纯化得到3.17g无色油状化合物(化合物7),产率86%浅棕色片状固体。1H NMR(500MHz,CDCl3):δ1.33(s,6H),1.42(s,6H),2.57(s,3H);13CNMR(125MHz,CDCl3):δ23.8,24.3,27.4,52.0,56.7,109.4,196.7,199.1,201.7,210.0。
化合物8的合成
将乙酰基β-三酮(化合物7,3.17g,14.2mmol)置于50mL的圆底烧瓶中,然后向其中加入6N的盐酸水溶液30mL。紧接着将反应体系置于110℃油浴中,剧烈搅拌并加热回流24个小时。待反应体系逐渐降至室温,然后将反应混合物用乙酸乙酯(50mL)萃取8次,合并有机相。所得到的有机相经无水硫酸钠干燥后过滤,旋转蒸发除去溶剂后,得到黄棕色油状物。该油状物经过快速柱层析(正己烷:乙酸乙酯=1:1)进一步纯化得到2.17g浅棕色粉末状固体化合物syncapic acid(化合物8),产率80%。syncapic acid:黄棕色粉末状固体;酮/烯醇异构的混合物,比例约为2:1。1H NMR(500MHz,CDCl3):酮:δ1.31(s,12H),3.61(s,2H);烯醇:δ1.40(s,12H),5.74(brd,J=2.3Hz,1H),8.00(br s,1H);13C NMR(100MHz,CDCl3):酮:δ21.8,50.2,59.1,204.3,208.9;烯醇:δ24.5,51.2,59.1,101.7,191.9,204.3,212.6.
化合物10的合成
向装有syncapic acid(182mg,1.0mmol)和异戊醛(172mg,2.0mmol)的20mL圆底烧瓶中加于无水二氯甲烷(10mL),均匀搅拌5分钟后,室温下向其中一次性加入脯氨酸(11.5mg,0.1mmol)。继续搅拌反应体系半个小时后,将反应完全后的混合物经过一段约3厘米长的硅胶层析柱(二氯甲烷作为洗脱剂)进行纯化,将能以当量的收率得到250mg无色油状化合物(化合物10)。i:无色油状物;1H NMR(500MHz,CDCl3):δ0.95(d,J=6.7Hz,6H),1.30(s,6H),1.31(s,6H),1.89(m,J=6.7Hz,1H),2.59(dd,J=3.0,3.0Hz,2H),7.51(dd,J=3.0Hz,1H);13C NMR(125MHz,CDCl3):δ21.9,22.3,22.6,28.7,38.9,57.9,58.6,133.1,159.1,196.4,199.5,208.8。
化合物11的合成
氢化钠(30.0mg,0.75mmol,60%矿物油中)慢慢地加入溶有酰基间苯三酚化合物(化合物6)(0.5mmol)的四氢呋喃溶液(5mL)中,然后加入溶有化合物10(不饱和酮)(62.5mg,0.25mmol)的四氢呋喃溶液(2mL)。混合物于室温下搅拌半个小时后,加入5mL 1N的盐酸水溶液。分离有机相,水相经乙酸乙酯(5mL)萃取3次,饱和食盐水(5mL)洗涤,无水硫酸钠干燥,旋转蒸发出去剩余的有机溶剂。剩余的粗产物再经过硅胶柱分离(正己烷:乙酸乙酯=10:1-2:1),将能以30-80%的产率得到所需要的目标产物11。
所述的化合物11,如式(2)所示:
当R为H时,所得化合物为式(2)中的11a;
当R为CH3时,所得化合物为式(2)中的11b;
当R为C2H5时,所得化合物为式(2)中的11c;
当R为C3H5时,所得化合物为式(2)中的11d;
当R为iPr时,所得化合物为式(2)中的11e;
当R为C4H9时,所得化合物为式(2)中的11f;
当R为iBu时,所得化合物为式(2)中的11g;
当R为C5H11时,所得化合物为式(2)中的11h;
当R为C6H13时,所得化合物为式(2)中的11i;
当R为C7H15时,所得化合物为式(2)中的11j;
当R为C8H17时,所得化合物为式(2)中的11k;
当R为C9H17时,所得化合物为式(2)中的11l;
当R为C10H21时,所得化合物为式(2)中的11m;
当R为C11H23时,所得化合物为式(2)中的11n;
当R为C13H27时,所得化合物为式(2)中的11o;
当R为C15H31时,所得化合物为式(2)中的11p;
当R为c-C4H7时,所得化合物为式(2)中的11q;
当R为c-C5H9时,所得化合物为式(2)中的11r;
当R为c-C6H11时,所得化合物为式(2)中的11s;
当R为CH2Ph时,所得化合物为式(2)中的11t;
当R为C2H4Ph时,所得化合物为式(2)中的11u;
具体结构如式(2)所示:
化合物11a-11u的表征数据如下所示:
1、化合物11a:2,4,6-trihydroxy-3-(1-(2-hydroxy-3,3,5,5-tetramethyl-4,6-dioxocyclohex-1-en-1-yl)-3-methylbutyl)benzaldehyde(11a).1H NMR(500MHz,CD3OD):δ=0.85(d,J=6.7Hz,3H),0.86(d,J=6.6Hz,3H),1.33(m,12H),1.43(m,1H),2.05(m,2H),4.45(t,J=7.5Hz,3H),5.75(s,1H)),10.1(s,1H);13C NMR(100MHz,CD3OD):δ=10.9,14.1,19.3,22.4,22.6,25.5,26.9,28.1,30.3,38.3,38.7,39.0,68.3,98.1,109.2,114.7,128.9,152.3,210.9,212.4.HRMS(ESI):calcd for C22H29O7 +,[M+H+]405.1906,found405.1913.
2、化合物11b:4-(1-(3-acetyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11b).1H NMR(400MHz,CDCl3):δ=0.86(m,6H),1.15-2.25(m,15H),2.72(s,3H),4.38(t,J=7.8Hz,1H);further peaksshow keto-enol tautomerism in a ratio of 4:6;enol tautomer:δ=5.97(s,1H),7.07(brs,1H),10.3(brs,1H),11.7(brs,1H);keto tautomer:δ=6.03(s,1H),7.07(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=21.8,22.3,22.6,24.2,25.4,26.2,26.9,27.0,27.0,27.9,32.2,38.2,48.7,55.1,97.9,104.1,108.7,114.8,159.5,162.5,164.3,176.6,203.3,204.0,212.5.HRMS(ESI):calcd for C23H31O7 +,[M+H+]419.2083,found 419.2070.
3、化合物11c:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-propionylphenyl)butyl)cyclohex-4-ene-1,3-dione(11c).1H NMR(400MHz,CDCl3):δ=0.85(d,J=6.5Hz,3H),0.86(d,J=6.5Hz,3H),1.20(t,J=7.2Hz,3H),1.27-1.45(m,10H),1.50(s,3H),1.75(m,1H),2.12(m,1H),3.15(q,J=7.2Hz,2H),4.38(t,J=7.7Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.95(s,1H),6.54(brs,1H),10.3(brs,1H),11.6(brs,1H);ketotautomer:δ=6.00(s,1H),6.54(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=8.6,22.3,22.4,22.6,24.2,26.1,26.8,27.0,27.9,36.9,38.2,48.6,55.1,97.9,103.3,108.9,114.8,159.1,162.5,163.8,176.6,203.2,207.3,212.5.HRMS(ESI):calcd for C24H33O7 +,[M+H+]433.2226,found 433.2258.
4、化合物11d:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-butyrylphenyl)butyl)cyclohex-4-ene-1,3-dione(11d).1H NMR(400MHz,CDCl3):δ=0.85(d,J=6.5Hz,3H),0.86(d,J=6.5Hz,3H),1.01(t,J=7.5Hz,3H),1.29-1.45(m,10H),1.50(s,3H),1.75(m,3H),2.13(m,1H),3.08(t,J=7.2Hz,2H),4.37(t,J=7.7Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enoltautomer:δ=5.93(s,1H),6.31(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.98(s,1H),6.31(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.0,18.1,22.3,22.6,22.8,24.3,26.1,26.8,26.9,27.9,29.0,29.3,29.4,38.2,45.5,48.6,55.1,98.0,103.6,109.0,114.8,114.9,158.8,162.8,164.3,176.6,203.2,206.6,212.5.HRMS(ESI):calcd for C25H35O7 +,[M+H+]447.2383,found 447.2380.
5、化合物11e:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-isobutyrylphenyl)butyl)cyclohex-4-ene-1,3-dione(11e).1H NMR(400MHz,CDCl3):δ=0.85(d,J=6.5Hz,3H),0.87(d,J=6.5Hz,3H),1.23(d,J=6.1Hz,6H),1.22(d,J=6.1Hz,3H),1.30-1.55(m,13H),1.55-1.86(m,3H),2.14(m,1H),3.95(m,1H),4.39(t,J=7.7Hz,1H);further peaks show keto-enol tautomerism in a ratioof 3:7;enol tautomer:δ=5.92(s,1H),6.05(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=5.98(s,1H),6.05(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.2,19.2,19.3,22.9,22.9,26.9,28.0,28.8,29.0,29.1,30.1,30.5,38.3,38.7,39.0,48.6,98.1,109.4,114.7,176.6,204.2,210.9,212.4.HRMS(ESI):calcd for C25H35O7 +,[M+H+]447.2383,found 447.2389.
6、化合物11f:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-pentanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11f).1H NMR(400MHz,CDCl3):δ=0.86(m,6H),0.95(t,J=7.3Hz,3H),1.25-1.45(m,13H),1.61-1.80(m,5H),2.12(m,1H),3.10(t,J=7.5Hz,2H),4.37(t,J=7.5Hz,1H);further peaks showketo-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.91(s,1H),6.02(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.97(s,1H),6.02(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=11.4,14.0,14.1,18.8,22.3,22.6,22.7,22.8,24.3,26.2,26.9,26.9,27.0,27.9,29.1,29.4,31.6,34.7,36.1,38.2,38.7,48.7,55.1,98.0,103.9,109.1,114.8,158.6,162.8,164.1,176.6,203.2,206.8,212.4.HRMS(ESI):calcd for C26H37O7 +,[M+H+]461.2539,found 461.2536.
7、化合物11g:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-(3-methylbutanoyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11g).1HNMR(400MHz,CDCl3):δ=0.85(d,J=6.5Hz,3H),0.86(d,J=6.5Hz,3H),1.01(d,J=6.6Hz,6H),1.29-1.45(m,10H),1.50(s,3H),1.78(m,1H),2.11(m,1H),,2.99(d,J=6.7Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.94(s,1H),6.79(brs,1H),10.4(brs,1H),11.6(brs,1H);ketotautomer:δ=6.00(s,1H),6.79(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,17.6,20.6,22.3,22.5,22.6,22.8,24.2,25.3,26.1,26.8,26.9,27.0,27.9,29.0,29.4,31.0,31.6,38.2,48.7,52.2,55.1,98.0,103.3,109.0,114.8,114.9,159.1,162.9,164.3,176.7,203.2,206.4,208.0,212.6.HRMS(ESI):calcd for C26H37O7 +,[M+H+]461.2539,found 461.2541.
8、化合物11h:4-(1-(3-hexanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11h).1H NMR(400MHz,CDCl3):δ=0.86(m,6H),0.92(t,J=7.1Hz,3H),1.16-1.45(m,15H),1.61-1.80(m,5H),2.12(m,1H),3.09(t,J=7.6Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.91(s,1H),5.98(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.97(s,1H),5.98(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.0,22.3,22.6,22.6,24.2,24.4,26.2,26.9,26.9,27.0,27.9,31.7,38.2,43.6,48.7,55.1,98.0,103.6,108.9,114.8,158.7,163.0,164.3,176.6,203.1,207.1,212.4.HRMS(ESI):calcd for C27H39O7 +,[M+H+]475.2696,found 475.2682.
9、化合物11i:4-(1-(3-heptanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11i).1H NMR(400MHz,CDCl3):δ=0.86(m,9H),1.16-1.45(m,16H),1.61-1.80(m,3H),2.10(m,1H),3.10(t,J=7.4Hz,2H),4.39(t,J=7.8Hz,1H);further peaks show keto-enol tautomerism in aratio of 3:7;enol tautomer:δ=5.96(s,1H),6.68(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=6.02(s,1H),6.68(brs,1H)10.6(brs,1H),11.3(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.6,24.3,24.7,25.6,26.2,26.9,27.0,28.0,29.2,30.3,31.4,31.7,38.3,38.7,43.6,48.7,55.1,98.0,103.5,109.0,114.8,115.0,158.8,162.7,164.0,176.7,203.2,206.9,212.5.HRMS(ESI):calcd for C28H41O7 +,[M+H+]489.2852,found 489.2855.
10、化合物11j:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-octanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11j).1H NMR(400MHz,CDCl3):δ=0.88(m,9H),1.16-1.45(m,18H),1.50(s,3H),1.61-1.80(m,3H),2.10(m,1H),3.11(t,J=7.4Hz,2H),4.39(t,J=7.8Hz,1H);further peaks show keto-enoltautomerism in a ratio of 3:7;enol tautomer:δ=5.97(s,1H),6.78(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=6.02(s,1H),6.89(brs,1H)10.6(brs,1H),11.3(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.6,22.7,24.3,24.8,26.9,27.0,29.2,29.5,31.8,38.3,43.6,48.7,55.1,98.0,103.5,108.9,114.8,115.0,159.1,162.7,163.9,176.7,203.2,207.0,212.6.HRMS(ESI):calcd for C29H43O7 +,[M+H+]503.3009,found 503.2999.
11、化合物11k:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-nonanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11k).1H NMR(400MHz,CDCl3):δ=0.88(m,9H),1.16-1.45(m,20H),1.50(s,3H),1.61-1.80(m,3H),2.13(m,1H),3.11(t,J=7.4Hz,2H),4.39(t,J=7.8Hz,1H);further peaks show keto-enoltautomerism in aratio of 3:7;enol tautomer:δ=5.96(s,1H),6.66(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=6.01(s,1H),6.67(brs,1H)10.6(brs,1H),11.3(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.6,22.7,24.3,24.8,26.9,27.0,29.2,29.5,31.9,38.2,43.6,48.7,55.1,98.0,103.6,109.0,114.8,115.0,159.0,162.7,164.0,176.7,203.2,206.9,212.5.HRMS(ESI):calcd for C30H45O7 +,[M+H+]517.3165,found 517.3160.
12、化合物11l:4-(1-(3-decanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11l).1H NMR(400MHz,CDCl3):δ=0.87(m,9H),1.16-1.45(m,22H),1.50(s,3H),1.61-1.80(m,3H),2.10(m,1H),3.09(t,J=7.5Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enoltautomerism in a ratio of 3:7;enol tautomer:δ=5.92(s,1H),6.32(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.98(s,1H),6.32(brs,1H),10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,25.6,26.2,26.9,27.0,27.9,29.1,29.3,29.5,29.5,31.9,38.2,43.6,48.7,55.1,98.0,103.6,109.1,114.8,158.8,162.7,164.0,176.6,203.2,206.9,212.4.HRMS(ESI):calcd forC31H47O7 +,[M+H+]531.3322,found 531.3341.
13、化合物11m:4-(1-(3-decanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11m).1H NMR(400MHz,CDCl3):δ=0.86(m,9H),1.16-1.45(m,24H),1.50(s,3H),1.61-1.80(m,3H),2.11(m,1H),3.09(t,J=7.4Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enoltautomerism in a ratio of 3:7;enol tautomer:δ=5.92(s,1H),6.29(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.98(s,1H),6.34(brs,1H),10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.4,22.6,22.7,24.8,26.2,26.9,27.0,29.3,29.5,29.5,29.6,29.6,31.9,38.2,43.6,48.7,49.0,55.1,98.0,103.7,109.1,114.8,115.0,158.8,162.8,164.1,176.6,203.2,206.9,212.5.HRMS(ESI):calcd forC32H49O7 +,[M+H+]545.3478,found 545.3476.
14、化合物11n:4-(1-(3-dodecanoyl-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11n).1HNMR(400MHz,CDCl3):δ=0.86(m,9H),1.16-1.45(m,26H),1.50(s,3H),1.61-1.80(m,3H),2.11(m,1H),3.09(t,J=7.4Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.94(s,1H),6.59(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=6.00(s,1H),6.66(brs,1H),10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,26.9,29.4,29.5,29.6,29.6,29.7,29.7,31.9,38.2,43.6,48.7,55.1,97.8,103.5,109.1,114.8,159.0,162.6,163.9,176.6,203.2,206.9,212.5.HRMS(ESI):calcd for C33H51O7 +,[M+H+]559.3635,found 559.3630.
15、化合物11o:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-tetradecanoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11o).1H NMR(400MHz,CDCl3):δ=0.86(m,9H),1.16-1.45(m,30H),1.50(s,3H),1.61-1.80(m,3H),,2.12(m,1H),3.09(t,J=7.5Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.91(s,1H),6.23(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=5.97(s,1H),6.22(brs,1H)10.6(brs,1H),11.2(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.6,22.7,24.2,24.3,26.2,26.9,27.0,27.9,29.4,29.5,29.6,29.6,29.7,29.7,38.2,38.7,43.6,48.8,55.1,98.0,109.1,114.8,162.6,164.3,202.9,207.1,212.7.HRMS(ESI):calcd for C35H55O7 +,[M+H+]587.3948,found 587.3798.
16、化合物11p:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-palmitoylphenyl)butyl)cyclohex-4-ene-1,3-dione(11p).1H NMR(400MHz,CDCl3):δ=0.86(m,9H),1.16-1.45(m,34H),1.49(s,3H),1.61-1.80(m,3H),2.10(m,1H),3.09(t,J=7.5Hz,2H),4.37(t,J=7.8Hz,1H);further peaks show keto-enoltautomerism in a ratio of 3:7;enol tautomer:δ=5.93(s,1H),6.60(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=6.00(s,1H),6.50(brs,1H)10.6(brs,1H),11.3(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,22.3,22.4,22.6,22.7,24.3,24.8,25.6,25.7,26.2,26.9,27.0,27.0,27.9,29.4,29.5,29.6,29.6,29.7,29.7,31.9,38.2,38.7,43.6,48.7,55.1,98.0,109.2,162.8,164.0,176.6,203.2,206.6,212.5.HRMS(ESI):calcdfor C37H59O7 +,[M+H+]615.4261,found 615.4226.
17、化合物11q:4-(1-(3-(cyclobutanecarbonyl)-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11q).1HNMR(400MHz,CDCl3+CD3OD):δ=0.86(m,6H),1.25-1.45(m,13H),1.60-2.50(m,8H),4.40(m,2H),δ=5.82(s,1H);13C NMR(100MHz,CDCl3+CD3OD):δ=17.5,22.4,22.6,24.6,24.8,25.3,25.5,27.1,28.9,30.0,31.6,38.4,38.8,46.3,46.5,52.0,54.1,69.7,96.4,111.7,112.7,157.0,163.2,178.7,207.6,208.0,211.4.HRMS(ESI):calcd for C26H35O7 +,[M+H+]459.2383,found 459.2393.
18、化合物11r:4-(1-(3-(cyclopentanecarbonyl)-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11r).1HNMR(400MHz,CDCl3):δ=0.86(m,6H),1.25-1.45(m,13H),1.60-1.95(m,10H),2.12(m,1H),4.08(m,1H),4.38(t,J=7.5Hz,1H);further peaks show keto-enol tautomerism in aratio of 3:7;enol tautomer:δ=5.91(s,1H),6.29(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=5.96(s,1H),6.29(brs,1H)10.6(brs,1H),11.3(brs,1H);13C NMR(100MHz,CDCl3):δ=22.4,22.6,24.3,26.2,26.2,26.9,26.9,29.2,30.2,48.9,50.1,53.7,55.0,69.9,98.1,109.4,114.8,158.9,163.2,163.9,176.9,204.7,209.6,211.2,212.4.HRMS(ESI):calcd for C27H37O7 +,[M+H+]473.2578,found 473.2566.
19、化合物11s:4-(1-(3-(cyclohexanecarbonyl)-2,4,6-trihydroxyphenyl)-3-methylbutyl)-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione(11s).1HNMR(400MHz,CDCl3):δ=0.86(m,6H),1.25-1.45(m,19H),1.78(m,3H),1.95(m,2H),2.12(m,1H),3.6(m,1H),4.37(t,J=7.5Hz,1H);further peaks show keto-enol tautomerismin a ratio of 3:7;enol tautomer:δ=5.92(s,1H),6.43(brs,1H),10.4(brs,1H),11.6(brs,1H);keto tautomer:δ=5.97(s,1H),6.43(brs,1H)10.6(brs,1H),11.3(brs,1H);13CNMR(100MHz,CDCl3):δ=14.1,22.3,22.5,22.7,22.8,24.3,26.1,26.1,26.9,26.9,28.0,29.2,29.5,29.6,31.6,31.7,38.3,38.7,48.7,49.3,53.6,55.1,98.1,109.2,114.8,114.9,158.9,163.4,164.0,176.7,203.1,210.1,211.4,212.5.HRMS(ESI):calcd forC28H39O7 +,[M+H+]487.2696,found 487.2722.
20、化合物11t:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-(2-phenylacetyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11t).1HNMR(400MHz,CDCl3):δ=0.87(m,6H),1.25-1.45(m,13H),1.75(m,1H),2.12(m,1H),4.38(t,J=7.5Hz,1H),4.46(m,2H),7.20-7.50(m,5H),;further peaks show keto-enoltautomerism in a ratio of 3:7;enol tautomer:δ=5.95(s,1H),6.24(brs,1H),10.2(brs,1H),11.7(brs,1H);keto tautomer:δ=6.00(s,1H),6.24(brs,1H),11.1(brs,1H);13C NMR(100MHz,CDCl3):δ=14.2,22.3,22.8,26.1,26.7,28.0,38.6,40.8,48.8,49.4,55.1,98.2,103.5,109.3,114.7,125.5,126.8,127.4,128.5,129.9,158.6,162.9,164.9,176.1,176.8,203.3,203.7,212.4.HRMS(ESI):calcd for C29H35O7 +,[M+H+]495.2383,found 495.2375.
21、化合物11u:5-hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-(3-phenylpropanoyl)phenyl)butyl)cyclohex-4-ene-1,3-dione(11u).1HNMR(400MHz,CDCl3):δ=0.87(m,6H),1.25-1.55(m,13H),1.77(m,1H),2.12(m,1H),3.05(t,J=7.5Hz,2H),3.46(t,J=7.5Hz,2H),4.39(t,J=7.5Hz,1H),7.20-7.35(m,5H);further peaks show keto-enol tautomerism in a ratio of 3:7;enol tautomer:δ=5.94(s,1H),6.24(brs,1H),10.3(brs,1H),11.6(brs,1H);keto tautomer:δ=6.00(s,1H),6.25(brs,1H)11.1(brs,1H);13C NMR(100MHz,CDCl3):δ=14.1,18.8,20.7,22.3,22.6,22.8,24.2,25.3,25.7,26.2,26.9,27.0,27.9,29.1,29.2,29.4,30.6,31.6,34.7,36.1,38.2,38.6,45.2,48.7,49.4,55.2,98.1,103.5,109.1,114.7,114.9,125.4,126.1,128.2,128.5,128.5,129.0,141.4,158.7,162.5,164.3,176.6,177.5,203.3,205.3,212.4.HRMS(ESI):calcd for C10H13O3 +,[M+H+]509.2539,found 509.2557.
实施例2:化合物的抗MRSA活性评价
本实施例将采用刃天青显色法测定样品抗MRSA活性的最低抑菌浓度(MIC)。试验中将使用96孔板稀释滴度技术,同时测定多种物质的最低抑菌浓度(MIC)。首先将7.5mL的指示剂溶液(100μg/mL的刃天青水溶液)与5mL的待测菌溶液(108CFU/mL)混匀,并向第1至第8列的所有测试孔中各加入100μL混合菌液。然后将100μL待测样品化合物11a-11u的DMSO溶液(64μg/mL)依次加入到第一列的各个板孔中,均匀混合后取出100μL的溶液转移到第二列相应的板孔中,并用同样的方法倍增稀释到第8列。最后,将加好样品的孔板放入到恒温培养箱,37℃培养10-12h。菌液变红色为无抑菌活性,蓝色为有抑菌活性,菌液维持蓝色的最低稀释浓度被认为是待测化合物的最低抑菌浓度。
结果如表1所示:
表1:化合物11a-11u的体外抗MRSA与SA的活性(MIC)
结果表明:绝大部分化合物都具有显著的抗MRSA活性。其中化合物11i-11n具有非常显著的其抗菌活性,它们的MIC值低达0.25-0.50μg/mL,比抗菌药“最后一道屏障”万古霉素(Vancomycin)1.0μg/mL好2-4倍。
实施例3:化合物的抗SA活性评价
本实施例将采用刃天青显色法测定样品抗SA活性的最低抑菌浓度(MIC)。试验中将使用96孔板稀释滴度技术,同时测定多种物质的最低抑菌浓度(MIC)。首先将7.5mL的指示剂溶液(100μg/mL的刃天青水溶液)与5mL的待测菌溶液(108CFU/mL)混匀,并向第1至第8列的所有测试孔中各加入100μL混合菌液。然后将100μL待测样品11a-11u的DMSO溶液(64μg/mL)依次加入到第一列的各个板孔中,均匀混合后取出100μL的溶液转移到第二列相应的板孔中,并用同样的方法倍增稀释到第8列。最后,将加好样品的孔板放入到恒温培养箱,37℃培养10-12h。菌液变红色为无抑菌活性,蓝色为有抑菌活性,菌液维持蓝色的最低稀释浓度被认为是待测化合物的最低抑菌浓度。
结果如表1所示,结果表明:绝大部分化合物都具有显著的抗SA活性。化合物11i-11n具有非常显著的其抗菌活性,它们的MIC值低达0.25-0.50μg/mL,比抗菌药“最后一道屏障”万古霉素(0.5μg/mL)好1-2倍。
实施例4:化合物的抗Bacillus cereus的活性评价
本实施例将采用刃天青显色法测定样品抗Bacillus cereus活性的最低抑菌浓度(MIC)。试验中将使用96孔板稀释滴度技术,同时测定多种物质的最低抑菌浓度(MIC)。首先将7.5mL的指示剂溶液(100μg/mL的刃天青水溶液)与5mL的待测菌溶液(108CFU/mL)混匀,并向第1至第8列的所有测试孔中各加入100μL混合菌液。然后将100μL待测样品11i-11p的DMSO溶液(64μg/mL)依次加入到第一列的各个板孔中,均匀混合后取出100μL的溶液转移到第二列相应的板孔中,并用同样的方法倍增稀释到第8列。最后,将加好样品的孔板放入到恒温培养箱,37℃培养10-12h。菌液变红色为无抑菌活性,蓝色为有抑菌活性,菌液维持蓝色的最低稀释浓度被认为是待测化合物的最低抑菌浓度。
结果如表2所示:
表2化合物11i-11p的体外抗菌活性(MIC)
结果表明:化合物11i-11p具有非常显著的抗Bacillus cereus活性,它们的MIC值为0.13-16μg/mL,跟抗菌药“最后一道屏障”万古霉素(0.5μg/mL)相当。
实施例5:化合物的抗B.subtilis、B.thuringiensis或Escherichia coli的活性评价
化合物11i-11p的抗B.subtilis、B.thuringiensis或Escherichia coli菌活性评价方法与操作过程跟实施例4的抗Bacillus cereus活性类似。其结果如表2所示,所有化合物显示出显著的广谱抗菌活性。
Claims (7)
1.开环桃金娘酮类似物,其结构如式(2)中的任一化合物:
2.权利要求1所述的开环桃金娘酮类似物中的任一化合物在制备抗菌药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述的抗菌药物为抗Methicillin-resistant Staphylococcus aureus、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli细菌的药物。
4.根据权利要求2或3所述的应用,其特征在于,所述的抗菌药物为抗细菌感染剂或防治细菌感染药物。
5.一种抗菌药物,其特征在于,含有权利要求1所述的开环桃金娘酮类似物中的任一化合物作为活性成份,和药学上可以接受的载体。
6.根据权利要求5所述的抗菌药物,其特征在于,所述的抗菌药物为抗Methicillin-resistant Staphylococcus aureus、Staphylococcus aureus、Bacillus cereus、B.subtilis、B.thuringiensis或Escherichia coli细菌的药物。
7.根据权利要求5或6所述的抗菌药物,其特征在于,所述的抗菌药物为抗细菌感染剂或防治细菌感染药物。
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