CN109111405B - 一种芳香硫醚类化合物及其农药和医药用途 - Google Patents
一种芳香硫醚类化合物及其农药和医药用途 Download PDFInfo
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Abstract
本发明涉及一种芳香硫醚类化合物及农药和医药用途。本发明的芳香硫醚类化合物具有很好的抑制医学白色念珠菌活性，本发明的芳香硫醚类化合物对SARS冠状病毒主蛋白酶具有很好的抑制活性，本发明的芳香硫醚类化合物具有很好的杀虫活性、抗农业病害真菌活性、抗农业植物病毒活性。可用于制备农用杀虫剂、农用杀菌剂或农用抗病毒剂，以及医用抗真菌药物或医用抗病毒药物。
Description
技术领域
本发明涉及一种芳香硫醚类化合物及其农药和医药用途，具体涉及一种芳香硫醚类化合物及其在制备农用杀菌剂方面的用途，在制备农用抗病毒剂方面的用途，在制备农用杀虫剂方面的用途，在制备医用抗真菌药物的用途和在抗SARS冠状病毒感染药物方面的用途。
技术背景
乙酰乳酸合成酶(acetohydroxyacid synthase，AHAS，E.C.2.2.1.6)是催化支链氨基酸缬氨酸、亮氨酸和异亮氨酸生物合成途经的第一个关键酶，该生命过程不存在于哺乳动物体内，因此靶向AHAS的抑制剂对人体具有生物安全性(Duggleby，R.G.，etal.J.Biochem.Mol.Biol. 2000，33，1-36)。在上世纪80年代，科学家们确认了乙酰乳酸合成酶可以作为除草剂的靶标之后，各个国家相继推出一系列AHAS抑制剂，当前世界范围内以AHAS为靶标的抑制剂有磺酰脲类(SU)、咪唑啉酮类(IMI)、三唑并嘧啶类(TP)、嘧啶水杨酸类(PTB)、磺酰胺羰基三唑啉酮类(SCT)，这些除草剂普遍具有低毒、杀草谱广以及选择性高的特点。其中嘧草硫醚除草剂本质上属于嘧啶水杨酸类化合物的一种。嘧草硫醚是日本组合化学公司研制，由组合化学公司、埯原公司和美国杜邦公司共同开发，于上世纪90年代上市的新一代广谱除草剂，目前主要用来防治棉花杂草包括马唐、稗草、牛筋草、和狗尾草等多种常见的杂草。嘧草硫醚是由一个4，6-二甲氧基嘧啶环以及水杨酸两部分以硫原子相连组成(Nezu，Y.，et al.J. Pesticide Sci.1999，24，217-229)。
某些含嘧啶环的化合物表现出很好的杀虫活性，如嘧啶威等(徐英等，农药，2011，50， 474-478)；某些含嘧啶环的化合物也表现出很好的杀菌活性，如甲基嘧菌胺等(陈美航等，农药，2017，474-477)；我们在此前研究发现，某些含有嘧啶环的二硫醚类化合物表现出如化合物3-32表现出很好的SARS冠状病毒主蛋白酶的抑制效果(Wang，J.G.etal.Eur.J.Med. Chem.2017，137，450-461)。
以上这些事实表明芳香硫醚类化合物可能表现出杀菌、杀虫、抗病毒活性。
嘧草硫醚、嘧啶威、甲基嘧菌胺以及化合物3-32的结构式如下所示。
发明内容
本发明的目的在于提供一种芳香硫醚类化合物及其农药和医药用途，特别是其在制备杀菌剂、杀虫剂和抗病毒剂的相关农药的用途，以及其在制备抗SARS冠状病毒感染、抗白色念珠菌感染的相关医药的用途。
本发明的芳香硫醚类化合物为：
本发明的芳香硫醚类化合物是通过下列反应式获得
对于条件A，指的是苯环含有氰基(-CN)取代的苯硫酚类为原料。这种情况下，将含有氰基取代的苯硫酚(1)在溶解在乙腈中，适量三乙基胺催化的条件下与2-氯-4，6-二甲氧基三嗪 (2)在室温下搅拌过夜，萃取后柱层析即得到目标化合物(3)，。
对于条件B，指的是苯环含有羧基(-COOH)的取代苯硫酚为原料。这种情况下，将含有羧基取代的苯硫酚(1)，2-氯-4，6-二甲氧基三嗪(2)和甲醇钠溶于甲醇中，加热回流5小时，萃取后柱层析后得到目标化合物(3)。
对于条件C，指的是杂环部分为嘧啶环。这种情况下，将取代苯硫酚(1)，2-甲磺酰基 -4，6-二甲氧基嘧啶(2)，催化量的四丁基溴化铵在95％乙醇溶液当中反应，通过饱和碳酸氢钠溶液调节pH＞7，加热回流15小时，萃取后柱层析后得到目标化合物(3)。
通过体内活性研究，本发明的芳香硫醚类化合物表现出很好抑制医学白色念珠菌效果。
通过离体酶抑制活性实验表明，本发明的芳香硫醚类化合物在对20μM浓度下SARS冠状病毒主蛋白酶的抑制效果十分明显。
通过农业杀虫活性实验研究，本发明的芳香硫醚类化合物在600μg/mL浓度下对粘虫有很好的防治效果。
通过抑制农业病害真菌活性研宄，本发明的芳香硫醚类化合物在50μg/mL浓度下对油菜菌核、辣椒疫霉、苹果纶纹、小麦纹枯、西瓜炭疽和水稻恶苗有很好的防治效果。
通过农业抗病毒活性研究，本发明的芳香硫醚类化合物在500μg/mL浓度下对烟草花叶病毒有很好的活体钝化作用。
本发明还提供一种农用杀虫剂，在有效剂量下，该杀虫剂能防除农业害虫，特别是粘虫。
本发明还提供一种农用杀菌剂，在有效剂量下，该杀菌剂能农业病源菌有很好的防效，特别是油菜菌核、辣椒疫霉、苹果纶纹、小麦纹枯、西瓜炭疽和水稻恶苗有很好的防效。
本发明还提供一种农用抗病毒剂，在有效剂量下，该抗病毒剂对烟草花叶病毒有很好的防效。
该农用杀虫剂、农用杀菌剂或农用抗病毒剂可含有与上述与芳香硫醚类化合物以及一种或多种农业上可接受的载体及盐类。其剂型为乳油、可湿性粉剂、可溶性粉剂、水乳剂、微乳剂、水剂、悬浮剂、微胶囊剂或水分散颗粒剂。其使用方式为茎叶处理或土壤处理。
本发明还提供一种用于预防和/或人或动物真菌感染的药物，特别是白色念珠菌(Candida albicans)，向真菌或其环境应用有效量的上述芳香硫醚类化合物，以此杀死真菌或控制真菌生长。
本发明还提供一种用于预防和治疗SARS病毒感染的药物，该药物通过抑制SARS冠状病毒主蛋白酶起到效果。
该医用抗真菌药物或医用抗病毒药物可含有上述芳香硫醚类化合物以及一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂以及增效剂等。该药物可以制成注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂的形式使用。其给药途径可为口服、经皮，静脉或肌肉注射。
附图说明
图1是化合物JGW6的单晶结构图。
具体实施方式
本发明实质性特点可以从下述实施例中得以体现，但这些实施例仅作为说明，而不是对本发明进行限制。
本发明使用的原料2-巯基-6-氟苯腈、2-巯基-6-氯苯腈、2-巯基-6-溴苯腈、2-巯基-6-碘苯腈、2-巯基-5-氟苯腈、2-巯基-5-氯苯腈、2-巯基-5-溴苯腈、3-氟-4-巯基苯腈、3-氯-4-巯基苯腈、3-溴-4-巯基苯腈、2-巯基-4-氯苯腈、2-巯基-4-三氟甲基苯腈、2-巯基-5-三氟甲基苯腈、 2-三氟甲基-4-巯基苯腈、2，4，6-三氯苯腈、3-三氟甲基-4-巯基苯腈、2-甲磺酰基-4，6-二甲氧基嘧啶、2-氯-4，6-二甲氧基-1，3，5-三嗪、2-巯基-5-氟苯甲酸、2-巯基-5-溴苯甲酸、3-氟-4-巯基苯甲酸、3-氯-4-巯基苯甲酸、3-溴-4-巯基苯甲酸、2-巯基-4-氟苯甲酸、2-巯基-4-氯苯甲酸、2- 巯基-4-溴苯甲酸、2-巯基-4，6-二氯苯甲酸、4-巯基-2，6-二氯苯甲酸、2-三氟甲基-4-巯基苯甲酸、2-巯基-4-三氟甲基苯甲酸和4-巯基-1，3-二苯甲酸等反应原料购自美国Aldrich化学品公司、美国Aurora化学品公司、拉脱维亚FCH化学品公司、上海Chemhere化学品公司，上海 Apichemical化学品公司，江苏HE Chemical化学品公司，其余原料和试剂均为天津本地市售。
实施例1.化合物JGW1的合成
在100mL的圆底烧瓶中加入2-巯基-6-氟苯腈0.48g(2.94mmol)，加入40mL乙腈将其溶解，室温搅拌下加入0.77g(4.4mmol)2-氯-4，6-二甲氧基三嗪，搅拌过夜。后处理：将反应体系旋干。将反应体系用乙酸乙酯和水相互萃取，提取乙酸乙酯层，加入硅胶粉旋干。反应物与产物的极性较为接近，利用80∶1(石油醚∶乙酸乙酯)的淋洗剂进行过柱。得到终产物JGW1为白色固体，质量为0.19g，产率22％。
同样的，可以合成化合物JGW2，JGW3，JGW4，JGW5，JGW6，JGW7，JGW8，JGW9， JGW10，JGW22，JGW32和JGW33。
实施例2.化合物JGW11的合成
加入0.28g(1.60mmol)2-巯基-5-氯苯甲酸，2-氯-4，6-二甲氧基三嗪0.42g(2.40mmol) 和0.26g(4.78mmol)甲醇钠于甲醇中，反应回流5h。反应后处理：将反应体系旋干后，用 NaOH水溶液和乙酸乙酯相互萃取三次，提取水层，用HCl调节pH至3-4之间，溶液变成白色乳浊液。之后用乙酸乙酯洗涤该水层两次，收集有机相乙酸乙酯，加入硅胶粉旋干。用80∶1 (二氯甲烷∶甲醇)的淋洗剂过柱。得到终产物JGW11为白色固体，质量0.08g，产率18％。
同样的，可以合成化合物JGW12，JGW13，JGW14，JGW15，JGW16，JGW25和JGW30。
实施例3.化合物JGW17的合成
加入0.48g(2.66mmol)2-巯基-5-氟苯甲酸，2-甲磺酰基-4，6-二甲氧基嘧啶0.87g(4.0mmol)，0.1g(0.3mmol)四丁基溴化铵于95％乙醇中，反应回流15h，反应每隔两小时测定一次pH 值，利用饱和NaHCO3水溶液调节pH值，使反应体系的pH值保持在7以上。反应后处理：将反应体系旋干，利用NaOH水溶液与乙酸乙酯相互萃取三次，提取水层，利用HCl调节pH值至3-4，此时水溶液变成乳白色的悬浊液。之后用乙酸乙酯萃取该水层，加入硅胶粉旋干过柱，利用80∶1(二氯甲烷∶甲醇)的淋洗剂过柱。得到产物0.15g，产率18％。
同样的，可以合成化合物JGW18，JGW19，JGW20，JGW21，JGW23，JGW24，JGW26，JGW27，JGW28，JGW29和JGW31。
化合物JGW1-JGW33的物化数据和结构表征数据见表1。
表1、化合物JGW1-JGW33的物化数据和波谱表征
实施例4.化合物对白色念珠菌最小抑制浓度MIC的测定
实验中采用的真菌菌株(标准株sc5314，临床株g5和17#)由中国科学院微生物研究所提供。
首先通过纸片扩散法来初步测定磺酰脲化合物的抗真菌活性。将10μL体积1nM的待测化合物置于接种板上，在35℃下培养24小时，48小时和72小时，读取抑制带。
再采用肉汤稀释法测定化合物对白色念珠菌的最小抑制浓度MIC(Ghannoum，M.A.et. Al.J.Clin.Microbiol.1992，30，2881-2886)。以无菌DMSO为溶剂配制化合物母液，使之在 YNB(Yeast Nitrogen Base without Amino Acids)培养基中的最终浓度为呈现一系列浓度梯度。 YNB培养基加入终浓度为0.5％的葡萄糖和100mM的硫酸铵。从培养48小时的培养皿上挑取1个真菌株于5mL的除菌水当中，在530nm下测量浑浊度，采用0.5％麦氏标准管将浊度调制1x106-5x106CFU/mL，然后接种液的浊度用YNB培养基稀释至约104CFU/mL，96孔板在35℃下培养72小时。分别在24小时、48小时和72小时读取浊度值，抑制真菌90％生长的浓度得以计算。每个浓度平行测定三次。
作为对照，也采用RPMI1640标准培养基对化合物的抑菌活性进行类似条件的测定，由于RPMI1640培养基当中含有支链氨基酸，可以评价支链氨基酸对化合物抑菌活性的影响。
表2给出了部分目标化合物以及对照化合物乙氧嘧磺隆在不同实验条件下对真菌菌株的抑制活性。
表2.目标化合物对不同来源的白色念珠菌的最小抑制浓度MIC值(μg/mL)
可以看出，本发明的化合物对于不同来源的白色念珠菌都有很好的抑制，在YNB培养基和1640培养基条件下所表现出来的活性不同，YNB当中活性更高。化合物JGW1对17# 的抑制与对照药乙氧嘧磺隆具有可比性。
实施例5、化合物的杀虫活性测定
浸叶法，配置后所需浓度后，把直径约为5-6cm的叶片浸入药液中5-6秒，取出，放在吸水纸上晾干，放在指定的培养皿中，接入10头粘虫3龄幼虫，放入27±1℃的养虫室中观察3-4天后检查结果。死亡率公式为：
目标化合物的杀虫效果见表3。
表3、部分目标化合物在600μg/mL浓度下对粘虫的杀虫效果(％)
| 编号 | 杀虫效果 | 编号 | 杀虫效果 | 编号 | 杀虫效果 |
| JGW1 | 20 | JGW2 | 5 | JGW3 | 75 |
| JGW4 | 45 | JGW5 | 20 | JGW6 | 0 |
| JGW7 | 20 | JGW8 | 0 | JGW9 | 30 |
| JGW10 | 30 | JGW11 | 80 | JGW12 | 40 |
| JGW13 | 45 | JGW14 | 30 | JGW15 | 20 |
| JGW16 | 10 | JGW18 | 65 | JGW19 | 30 |
| JGW20 | 50 | JGW21 | 50 | JGW22 | 25 |
| JGW23 | 65 | JGW24 | 30 | JGW25 | 80 |
| JGW26 | 60 |
可以看出，本发明的化合物在600μg/mL浓度下对粘虫有很好的杀虫效果，其中化合物 JGW11和JGW25的杀虫活性高达80％。
实施例6、化合物抑制农业病害真菌活性测定
以油菜菌核菌为例，可以换成其他农业病害真菌。
离体测试方法：将油菜菌核病菌接到PDA培养基上培养7天，用打孔器在菌落边缘制取直径4cm的菌碟接种到含有50μg/mL和不含药剂的PDA培养基上培养4天，量取菌落直径，与对照比较计算出药剂的抑制百分率。
表4给出了部分化合物抑制植物不同农业病害真菌的效果。
表4、目标化合物在50μg/mL浓度下对农业病害真菌的抑制效果(％)
可以看出，本发明的多数化合物对于农作物病害真菌有很好的抑制效果，有部分化合物在50μg/mL浓度下的杀菌率＞80％。
进一步测定了部分高活性化合物抑制小麦锈病的EC50值，对照化合物为嘧草硫醚，结果见表5。
表5.部分高活性化合物抑制小麦锈病的EC50值(μg/mL)
| 小麦纹枯 | EC<sub>50</sub>值 | 小麦纹枯 | EC<sub>50</sub>值 |
| JGW10 | 12.4483 | JGW20 | 9.2004 |
| JGW19 | 11.7896 | JGW21 | 11.3503 |
实施例7、化合物抗烟草花叶病毒(TMV)活性的测定
病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。病毒粗提液经2次聚乙二醇离心处理后，测定浓度，4℃冷藏备用。称量目标化合物后，原药加入 DMF溶解，制得1×105μg/mL母液，后用含1‰吐温80水溶液稀释至所需浓度；宁南霉素制剂直接兑水稀释。选长势均匀一致的3-5叶期珊西烟，将药剂与等体积的病毒汁液混合钝化30分钟后，摩擦接种，病毒浓度20μg/mL，接种后即用流水冲洗，重复3次，设1‰吐温80水溶液对照。3天后数病斑数，计算活体钝化效果。
抑制率(％)＝[(对照枯斑数-处理枯斑数)/对照枯斑数]×100％
目标化合物与对照药剂病毒唑和宁南霉素的抗TMV活性结果见表6。
表6、部分目标化合物对TMV的活体钝化防治效果(％)
可以看出，本发明的化合物对于烟草花叶病毒TMV有很好的活体钝化防治效果，其中化合物JGW17、JGW19和JGW25在500μg/mL浓度下防效优于商品药剂病毒唑。
实施例8、目标化合物抗SARS冠状病毒主蛋白酶抑制活性的测定
本发明采用的SARS冠状病毒主蛋白酶的表达、纯化等方法步骤参考文献方法(Rao，Z.H. et al.，PNAS，2003，100，13190-13195)，筛选方法是饶子和等在CN101418334A中公开的筛选方法。SARS冠状病毒主蛋白酶的活性测定是使用荧光底物MCA-AVLQSGFR-Lys(Dnp) -Lys-NH2来完成的。该荧光底物的氨基酸序列来源于SARS冠状病毒主蛋白酶的N端自剪切序列。用于荧光强度测定的仪器为Fluoraskan Ascent荧光仪(Thermo)，激发光和发射光的波长分别为320nm和405nm。
用于酶反应的缓冲体系是50mM Tris-HCl(pH 7.3)，1mM EDTA(不含DTT)，用缓冲液配置冠状病毒主蛋白酶(总浓度1μM)，加入备选样品DMSO溶解物(终浓度为10μM)，303k放置10min，迅速加入荧光底物MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2，底物浓度为20μM。每5s记录一次荧光读数，共测定200个点。1200rpm震荡5s，检测荧光值。不加备选样品，其余实验条件均相同。
以时间为X轴，荧光值为Y轴可得酶活动力学曲线。通过酶标仪记录的酶反应的相关参数，根据荧光强度以及反应时间，采用GraphPad Prism 5软件分析前10s的酶促反应的速率。设定V0为不加抑制剂的酶促反应的初速度，Vi为加抑制剂的酶促反应的初速度。根据酶促反应速率，计算出每个化合物的剩余活性Ra(Residual Activity，Ra)(Vi/V0)以及抑制率Ir (Inhibition Rate，Ir)(1-Vi/V0)。
对于剩余活性＜20％的化合物进行复筛，排除假阳性的可能。对于剩余活性低于15％的化合物，设计荧光淬灭实验。综合考虑化合物的剩余活性百分率和荧光淬灭率就可以判断化合物对SARS冠状病毒主蛋白酶的抑制作用。
因为该体系主要是通过荧光强度来筛选的，所以，当有荧光的化合物或者是与MCA类似的化合物都会对体系产生干扰。另外，很多Dnp类似的结构会淬灭体系的荧光而造成假阳性，为了排除假阳性结果，我们采用先将主蛋白酶与荧光底物反应一段时间，让体系荧光达到最大值Q1，再在体系中加入与实验组等量的化合物，并检测体系的荧光值大小为Q2。将两者的荧光值按照公式计算得出荧光淬灭率Qr(Qr＝(Q1-Q2)/Q2*100％)。当荧光淬灭率高于20％为假阳性结果需排除，当荧光淬灭率低于20％为阳性结果，可以进行下一步研究。
目标化合物对SARS冠状病毒主蛋白的抑制率见表7。
表7、部分化合物在20μM浓度下对SARS冠状病毒主蛋白的抑制率(％)
| 编号 | 抑制率 | 编号 | 抑制率 | 编号 | 抑制率 |
| JGW1 | 90.8 | JGW2 | 76.6 | JGW3 | 96.3 |
| JGW4 | 98.4 | JGW5 | 100 | JGW6 | 85.1 |
| JGW7 | 100 | JGW11 | 94.5 | JGW12 | 24.2 |
| JGW13 | 48.8 | JGW14 | 89.5 | JGW15 | 25.5 |
| JGW16 | 25 | JGW19 | 26.8 | JGW22 | 29.9 |
| JGW24 | 84.7 | JGW25 | 21.7 | 嘧草硫醚 | 9.1 |
可以看出，本发明的化合物对SARS冠状病毒主蛋白有很强的抑制，在20μM浓度下，化合物JGW1，JGW3，JGW4，JGW5，JGW7，JGW11这几个化合物的抑制率均＞90％。
Claims (11)
1.一种芳香硫醚类化合物，其特征在于该化合物为
2.权利要求1所述的一种芳香硫醚类化合物在制备农用杀虫剂方面的用途。
3.权利要求1所述的一种芳香硫醚类化合物在制备农用杀菌剂方面的用途。
4.权利要求1所述的一种芳香硫醚类化合物在制备农用抗病毒剂方面的用途。
5.权利要求1所述的一种芳香硫醚类化合物在制备医用抗白色念珠菌药物方面的用途。
6.权利要求1所述的一种芳香硫醚类化合物在制备医用抗SARS病毒感染药物方面的用途。
7.根据权利要求6所述化合物的应用，其中所述化合物是SARS冠状病毒主蛋白酶的小分子抑制剂。
8.一种农用杀虫剂、农用杀菌剂或农用抗病毒剂，其特征在于它含有权利要求1所述的一种芳香硫醚类化合物以及农业上可接受的载体。
9.根据权利要求8所述的农用杀虫剂、农用杀菌剂或农用抗病毒剂，其特征在于其剂型为乳油、可湿性粉剂、可溶性粉剂、水乳剂、微乳剂、水剂、悬浮剂、微胶囊剂或水分散颗粒剂。
10.一种医用抗生素或医用抗病毒药物，其特征在于它含有权利要求1所述的一种芳香硫醚类化合物以及一种或多种药学上可接受的载体；所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或增效剂。
11.根据权利要求10所述的医用抗生素或医用抗病毒药物，其特征在于它是含有所述医用抗生素或医用抗病毒药物的注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂。
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