CN112110907B - 一种含1,4-二氧六环二聚双噻吩结构的化合物及其制备方法和应用 - Google Patents
一种含1,4-二氧六环二聚双噻吩结构的化合物及其制备方法和应用 Download PDFInfo
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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- A01N43/24—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with two or more hetero atoms
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Abstract
本发明涉及一种含1,4‑二氧六环二聚双噻吩结构的化合物及其制备方法和应用。该化合物具有式(1)所示的结构,制备方法包括以下步骤:(1)将驴欺口干燥根利用乙醇提取,得到乙醇浸膏;(2)将乙醇浸膏采用硅胶柱色谱,依次以正己烷‑丙酮和石油醚‑丙酮为洗脱剂进行梯度洗脱得到馏分;(3)将步骤(2)获得的馏分采用羟丙基葡聚糖凝胶以氯仿‑甲醇洗脱,最后用制备薄层色谱得到一种含1,4‑二氧六环二聚双噻吩结构的化合物。本发明首次提供该化合物,并发现该化合物物在农药等领域具有广泛应用。
Description
技术领域
本发明涉及植物化学技术领域,具体涉及一种从驴欺口提取分离的含1, 4-二氧六环二聚双噻吩结构的化合物及其在杀线虫和抗植物病原真菌中的应用。
背景技术
植物资源是农药开发的重要源泉。植物源农药在农作物病虫害防治中具有对环境友好、毒性普遍较低、不易使病虫产生抗药性等优点,是生产无公害农产品应优先选用的农药品种。
驴欺口(Echinops latifolius Tausch.)为菊科(Compositae)蓝刺头属(Echinops)植物。驴欺口花色蓝黄,花形美观,是一种观赏价值很高的园林植物。此外,该植物的根由于具有抗炎和促进泌乳的作用,长期以来一直被用作中药,并被收录在″中国药典″中,作为禹州漏芦的来源之一。
迄今为止,国内外研究者已从驴欺口干燥根中分离得到多种结构类型化合物,主要包括噻吩、苯丙素类、萜类(单萜、倍半萜、二萜等)、甾体类、生物碱类以及脂肪酸类等。其中天然噻吩是一类很小的天然化合物,大多数都是由一到三个噻吩环通过其α-碳偶联在一起,并在它们的自由邻位上携带烷基链。到目前为止,已鉴定了150多个噻吩衍生物。它们可以根据噻吩环的数量进行结构分类,包括单噻吩(一环)、二噻吩(二环)、三噻吩(三环)。具有四个噻吩环的二联噻吩二聚体是非常罕见的,特别是通过1,4- 二氧六环的新骨架来连接两个二联噻吩单元的二聚体是未见报道的。噻吩类化合物是作为许多植物物种化学防御机制的一部分产生的,被认为是合成农药的天然替代品的潜在来源。因此,从驴欺口干燥根中分离提取出含有1, 4-二氧六环的二联噻吩二聚体化合物并阐明其杀线虫和抗植物病原真菌具有重要的现实意义。
目前,未见有本发明化合物的相关报道,更未见有将本发明化合物用于杀线虫和抗植物病原真菌的农用活性的相关报道。
发明内容
鉴于现有技术所存在的问题,本发明提供一种含1,4-二氧六环二聚双噻吩结构的化合物及其制备方法和应用。该化合物具有农药应用价值,以及包含该含1,4-二氧六环二聚双噻吩的新骨架化合物的药物组合物,以便为杀线虫和抗植物病原真菌提供更多的药物选择途径。
本发明解决上述技术问题的技术方案如下:
一种含1,4-二氧六环二聚双噻吩结构的化合物,命名为 EchinbithiophenedimerC,式(1);具有如下结构:
本发明进一步提供了式(1)所示的化合物的晶型、立体异构体、药学上可接受的盐、溶剂合物、前体药物或代谢产物。
本发明还提供一种农药组合物,包括上述式(1)的含1,4-二氧六环二聚双噻吩结构的化合物、或其晶型、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物,以及药学上可接受的辅料。根据不同的剂型,组合物中上述式(1)所示结构的化合物的含量可以为0.5-30wt%,其余为药学上可接受的辅料。
本发明所述药学上可接受的辅料,是指除活性成分以外包含在剂型中的物质。药学上可接受的辅料包括任意通常使用的农药用辅料,在液体制剂的情况下,例如有机溶剂如丙酮、吐温水溶液(例如0.1%(V/V)吐温-80水溶液)等,上述式(1)所示结构的化合物在最终使用的液体制剂中质量浓度例如可以是0.5-5wt%。在可湿性粉剂的情况下,例如包括白炭黑、十二烷基硫酸钠、CMC十二烷基硫酸钠、拉开粉、凹凸棒土,上述式(1)所示结构的化合物在可湿性粉剂中的含量可以为15-30wt%。
在一个实施方案中,可湿性粉剂包括上述式(1)所示结构的化合物粉末15-25wt%,白炭黑15-25wt%,十二烷基硫酸钠2-8wt%,CMC十二烷基硫酸钠0.5-2wt%和拉开粉1-6wt%,凹凸棒土余量;优选地,上述式 (1)所示结构的化合物的粉末20wt%,白炭黑20wt%,十二烷基硫酸钠 5wt%,CMC十二烷基硫酸钠1wt%和拉开粉3wt%,凹凸棒土余量。
本发明的一种或多种化合物可以彼此联合使用,也可选择将本发明的化合物与任何其它的活性试剂结合使用。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明还提供上述含1,4-二氧六环二聚双噻吩结构的化合物的制备方法,包括以下步骤:
(1)将驴欺口干燥根利用乙醇提取,得到乙醇浸膏;
(2)将乙醇浸膏采用硅胶柱色谱,用正己烷-丙酮为洗脱剂进行梯度洗脱得到馏分;
(3)将步骤(2)获得的馏分采用羟丙基葡聚糖凝胶硅胶柱层析和薄层制备色谱制备,得到含1,4-二氧六环二聚双噻吩结构的化合物。
具体的,步骤(2)的具体操作步骤可以为:
取步骤(1)所得乙醇浸膏,采用硅胶柱色谱,以正己烷-丙酮体积比 (15∶1)~(1∶1)为洗脱剂进行梯度洗脱,收集洗脱液作为馏分。
具体的,可以采用下面的具体步骤进行制备一种含1,4-二氧六环二聚双噻吩结构的化合物:
(A)取驴欺口干燥根,粉碎,用乙醇回流提取,合并提取液减压浓缩得乙醇浸膏;
(B)取步骤(1)所得乙醇浸膏,采用硅胶柱色谱,依次以正己烷-丙酮体积比15∶1、10∶1、3∶1、1∶1为洗脱剂进行梯度洗脱,得到四个组分FA-FD,经薄层色谱进行检测,显色,合并相同洗脱部位,将合并后的洗脱部位经减压浓缩至干,备用;
(C)将步骤(B)中FB组分再经硅胶柱色谱,以体积比为(10∶1)~(1∶1)的石油醚-丙酮溶剂梯度洗脱,薄层色谱检测,显色,合并相同洗脱部位,再经羟丙基葡聚糖凝胶色谱,以体积比为(1∶1)的氯仿-甲醇洗脱,薄层色谱检测,显色,合并相同洗脱部位,得到三个馏分FBA-FBC;
(D)将步骤(C)中所得FBB馏分,以石油醚-正己烷-丙酮(5∶1∶0.5) 为展开剂,采用制备薄层色谱制备得到化合物Echinbithiophenedimer C。
优选的,步骤(B)中,收集以正己烷-丙酮体积比为10∶1的洗脱剂进行洗脱所获的洗脱液作为馏分。
优选的,步骤(C)中,收集以石油醚-丙酮体积比为8∶1洗脱剂进行洗脱所获的洗脱液作为馏分。
本发明还提供了上述式(1)的含1,4-二氧六环二聚双噻吩结构的化合物、或其晶型、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备农药中的应用。进一步地,所述农药为防治线虫的农药或防治植物病原真菌(链格孢菌、稻瘟病菌、尖孢镰刀菌、球孢炭疽菌和马铃薯晚疫病菌等)的农药。
上述一种含1,4-二氧六环二聚双噻吩结构的化合物可以在制备杀线虫农药中进行应用,发明人在研究过程中意外的发现,其杀线能力优于现有杀线农药灭线磷的杀线能力。说明含1,4-二氧六环二聚双噻吩的新骨架化合物作为植物源农药在杀线虫方向具有较好的应用前景。可以进一步制备成杀线虫植物源农药用于线虫防治。
上述含1,4-二氧六环二聚双噻吩结构的化合物可以在制备抗植物病原真菌农药中进行应用。可以进一步制备成抗植物病原真菌植物源农药用于病原真菌防治。
在应用的过程中,可以根据实际的使用要求,将含1,4-二氧六环二聚双噻吩结构的化合物制备成合适的剂型或添加一种或几种本领域常规的辅料以制成药物组合物进行应用。
试验结果表明,本发明化合物具有较好的杀线虫和抗植物病原真菌作用,为农业上筛选和/或制备杀线虫、抗植物病原真菌提供了一种新的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更,修改、替换或变更后的方案也在本发明保护范围内。
附图说明
图1为式(1)所示化合物的1H NMR谱图。
图2为式(1)所示化合物的13C NMR谱图。
图3为式(1)所示化合物的核磁共振HSQC光谱图。
图4为式(1)所示化合物的核磁共振HMBC光谱图。
图5为式(1)所示化合物的HRESIMS质谱图。
图6为式(1)所示化合物的红外光谱图。
具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
若无特殊说明,本发明具体实施方式所使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1制备本发明所述化合物
1、实验材料:
①药材
驴欺口根于2017年9月采自北京市门头沟,鉴定为菊科蓝刺头属植物驴欺口(Echinops latifolius Tausch.)的干燥根。
②试剂和填料
柱层析硅胶,200~300目(试剂级),购于青岛海洋硅胶干燥剂厂;
薄层层析硅胶GF254(化学纯),购于青岛海洋硅胶干燥剂厂;
Sephadex LH-20葡聚糖凝胶,购于瑞典Amersham公司;
GF254硅胶制备薄层,购于烟台江友硅胶开发有限公司;
石油醚、正己烷、三氯甲烷、乙酸乙酯、丙酮、甲醇等分析纯试剂,购于北京化工厂。
③实验仪器
Bruker-AVIIIHD-600核磁共振仪(瑞士Bruker);Nicolet 5700红外光谱仪(美国Thermo公司);Perkin-Elmer 341旋光测定仪(美国 PerkinElmer);BP211D十万分之一电子天平(瑞士Sartorius);R-210旋转蒸发器(瑞士BUCHl);DZG-6050型真空干燥箱(上海森信)。
2、成分的分离纯化:
1)取驴欺口干燥根1.8kg,粉碎后,用乙醇回流提取3次,合并提取液,减压浓缩得到乙醇浸膏90g;
2)取步骤1)中所得乙醇浸膏,采用硅胶柱色谱(柱层析硅胶,200~ 300目(试剂级),购于青岛海洋硅胶干燥剂厂),依次以正己烷-丙酮体积比 15∶1、10∶1、3∶1、1∶1为洗脱剂进行梯度洗脱,经薄层色谱进行检测,显色,合并相同洗脱部分,得到4个组分,FA-FD。(FA为正己烷-丙酮15∶1的馏分,FB为正己烷-丙酮10∶1的馏分,FC为正己烷-丙酮3∶1的馏分,FD为正己烷-丙酮1∶1的馏分,共4个组分)
3)将步骤2)中FB组分再经硅胶柱色谱(Sephadex LH-20葡聚糖凝胶),以体积比为(10∶1)~(1∶1)的石油醚-丙酮梯度洗脱,薄层色谱检测,10%硫酸乙醇显色剂显色,根据Rf值和显色颜色合并相同洗脱部分,得到3个馏分FBA-FBC(FBA为石油醚-丙酮10∶1的馏分,FBB为以石油醚-丙酮5∶1的馏分,FBC为石油醚-丙酮1∶1的馏分)。
4)将步骤3)中所得FBB馏分,以石油醚-正己烷-丙酮(5∶1∶0.5) 为展开剂,采用制备薄层色谱(GF254硅胶制备薄层)制备得到化合物 Echinbithiophenedimer C。
3、化合物的鉴定:
在分离得到各化合物后,对其理化性质和分子结构进行了鉴定,得到化合物1为一种含1,4-二氧六环二聚双噻吩的新骨架化合物,其具体理化性质和波谱数据如下:
Echinbithiophenedimer C(3):黄色不定型固体;(c 0.1,MeOH);UV(CH3CN)λmax(log ε)245(0.17),338(0.63)nm;ECD(CH3CN) λmax(Δε)208(-13.4),255(+3.5)nm;IR(KBr)Vmax1650 and 1026 cm-1;HR-ESI-MS[M+Na]+m/z 515.0240(calcdfor C26H20NaO2S4,515.0238).
4、核磁共振氢谱(1H-NMR):Bruker-AVIII HD-600spectrometer测定,数据见表1。
5、核磁共振碳谱(13C-NMR):Bruker-AVIII HD-600spectrometer测定,数据见表1。
表1 Echinbithiophenedimer C的1H-NMR(600MHz)、13C-NMR(150MHz)核磁数据
(测定溶剂:CDCl3;δ:ppm;J:Hz)
为了说明本发明的有益效果,本发明进一步提供以下实施例。
实施例2:对南方根结线虫二龄幼虫的毒力测定
1)样品的配置:
待测化合物及商用杀线剂灭线磷用丙酮溶解制备成浓度为104μg/mL 的母液。用0.1%(V/V)吐温-80水溶液稀释待测化合物,保证最终待测化合物中有机溶剂含量不超过1%(V/V)。
2)南方根结线虫二龄幼虫的准备:
采集被南方根结线虫(M.incognita)侵染的番茄根,用灭菌的蒸馏水轻洗番茄根,于体视显微镜下,用镊子轻轻剥离卵块,置于含有少量蒸馏水的培养皿内,28℃培养箱孵化3-5天。孵化出的2龄根结线虫线虫可用作生物测定的目标生物。
3)生物活性测定:
取96孔生化测试板,各取100μL供试药液置于小孔中,加入等体积的线虫悬浮液,保证每孔二龄线虫数80-100头,盖板以防水分蒸发。96 孔板置于28℃培养箱,避光。每个处理重复4次。处理24小时后检查南方根结线虫二龄幼虫的存活数量和死亡数量,计算死亡率和校正死亡率。并用 SAS软件计算出药剂的LC50。死亡率和校正死亡率按如下公式计算:
4)生测结果:
表2 Echinbithiophenedimer C对南方根结线虫的毒性(μg/mL)
试验结果表明,
从表2的数据可以看出,Echinbithiophenedimer C对对南方根结线虫二龄幼虫都有不同程度的杀线活性。并且发明人意外的发现 Echinbithiophenedimer C优于现有商业杀菌剂灭线磷。可以进一步制备成杀线农药。
实施例3:抗植物病原真菌活性测试
1)样品的配置:
待测化合物及商用杀菌剂多菌灵用有机溶剂丙酮溶解制备成浓度为104μg/mL的母液。用0.1%(V/V)吐温-80水溶液稀释待测化合物,保证最终待测化合物中有机溶剂含量不超过1%(V/V)。
2)病原真菌的准备:
链格孢菌(Alternaria alternate)、稻瘟病菌(Pyricularia oryzae)、尖孢镰刀菌(Fusarium oxysporum)、球孢炭疽菌(Colletotrichum gloeosporioides)和马铃薯晚疫病菌(Phytophthora infestans)为主要病原菌来测试抗真菌活性。
3)生物活性测定:
用马铃薯葡萄糖(PD)培养基用微量肉汤稀释法测定96孔板的抗真菌活性。简单地说,每个纯化的化合物从256μg/mL开始依次稀释到含有真菌病原体孢子悬浮液(1×106CFU)的96孔板的孔中,用微量肉汤稀释法测定抗真菌活性。简单地说,每个纯化的化合物从256μg/mL开始依次稀释到含有真菌病原体孢子悬浮液(1×106cfu)的96孔板中。以多菌灵为阳性对照。在28±0.5℃黑暗中培养3d后,以最低抑菌浓度(MIC)作为试验化合物在96孔板中的最低浓度下无微生物生长。在所调查的所有浓度下,对每种化合物进行三次重复测定。
4)生测结果:
表3 Echinbithiophenedimer C抗植物病原真菌活性(MIC,μg/mL)
A.a.,Alternaria alternate(链格孢菌);P.o.,Pyricularia oryzae(稻瘟病菌);F.o.,Fusarium oxysporum(尖孢镰刀菌);C.g.,Colletotrichum gloeosporioides(胶孢炭疽菌);P.i.,Phytophthora infestans(马铃薯晚疫病菌)。
表3数据表明,化合物Echinbithiophenedimer C(MIC=8μg/mL) 对链格孢菌和稻瘟菌的抗真菌活性优于阳性对照多菌灵(MIC=16μg/mL)。化合物EchinbithiophenedimerC对尖孢镰刀菌和球孢炭疽菌均有较好的抑菌活性(MIC值为16-64μg/mL)。化合物Echinbithiophenedimer C对致病疫霉的MIC值为128μg/mL,优于多菌灵(MIC值为256μg/mL)。
实施例4:可湿性粉剂
配方(重量比)及制备方法:实施例1所得化合物的粉末20%,白炭黑20%,十二烷基硫酸钠5%,CMC十二烷基硫酸钠1%和拉开粉3%,凹凸棒土余量。将上述原料混合均匀,控制加工温度0-50℃,在气流粉碎机或其它高目粉碎机中,粉碎到150目以上,水分控制在6-8%(质量百分含量),pH控制在7-7.5。即可制得20%式(1)所示化合物的可湿性粉剂。经制剂的水中分散性、稀释液稳定性、冷热贮稳定性符合商品农药制剂的要求。经验证具有很好的杀线和抑制植物病原真菌能力。
综上所述,本发明提供一种含1,4-二氧六环二聚双噻吩的新骨架化合物及其提取分离方法,该化合物由于其独特的化学结构,并从常用中药驴欺口中提取出来,实验结果表明其具有杀线虫和抗植物病原真菌活性,因此作为植物源天然产物在农药领域具有广阔的应用前景。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (7)
2.一种农药组合物,其包括权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物或其药学上可接受的盐,以及药学上可接受的辅料。
3.根据权利要求2所述的农药组合物,其中,该农药组合物为液体制剂,权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物在液体制剂中质量浓度为0.5-5wt%;或者该农药组合物为可湿性粉剂,权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物在可湿性粉剂中的含量为15-30wt%。
4.根据权利要求3所述的农药组合物,其中,可湿性粉剂包括权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物粉末15-25wt%,白炭黑15-25wt%,十二烷基硫酸钠2-8wt%,CMC十二烷基硫酸钠0.5-2wt%和拉开粉1-6wt%,凹凸棒土余量。
5.权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物的制备方法,包括以下步骤:
(A)取驴欺口干燥根,粉碎,用乙醇回流提取,合并提取液减压浓缩得乙醇浸膏;
(B)取步骤(A )所得乙醇浸膏,采用硅胶柱色谱,依次以正己烷-丙酮体积比15:1、10:1、3:1、1:1为洗脱剂进行梯度洗脱,得到四个组分FA、FB、FC和FD,经薄层色谱进行检测,显色,合并相同洗脱部位,将合并后的洗脱部位经减压浓缩至干,备用;
(C)将步骤(B)中FB组分再经硅胶柱色谱,以体积比为10:1~1:1的石油醚-丙酮溶剂梯度洗脱,薄层色谱检测,显色,合并相同洗脱部位,再经羟丙基葡聚糖凝胶色谱,以体积比为1:1的氯仿-甲醇洗脱,薄层色谱检测,显色,合并相同洗脱部位,得到三个馏分FBA、FBB和FBC;
(D)将步骤(C)中所得FBB馏分,以石油醚-正己烷-丙酮5:1:0.5为展开剂,采用制备薄层色谱制备得到含1,4-二氧六环二聚双噻吩结构的化合物。
6.根据权利要求5所述的制备方法,其中,步骤(C)中,收集以石油醚-丙酮体积比为8:1洗脱剂进行洗脱所获的洗脱液作为馏分。
7.权利要求1所述的含1,4-二氧六环二聚双噻吩结构的化合物或其药学上可接受的盐在制备防治线虫的农药或防治植物病原真菌的农药中的应用。
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