CN107089975B - 含1,3,4-噁二唑基的噻唑盐类化合物及其制备方法及应用 - Google Patents
含1,3,4-噁二唑基的噻唑盐类化合物及其制备方法及应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Agronomy & Crop Science (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种含1,3,4‑噁二唑基的噻唑盐类化合物及其制备方法及应用，该化合物具有如通式(I)所示的结构：
Description
技术领域
本发明涉及药物化学技术领域，尤其是一种含1,3,4-噁二唑基的噻唑盐类化合物及其制备方法与应用。
背景技术
近年来，随着生态条件、品种和耕作制度的不断改变，植物细菌性病害(如水稻白叶枯病、烟草青枯病和柑橘溃疡病等)在我国大规模发生并流行，并在全国有进一步扩散蔓延趋势，为害范围广，防治困难，现有商品化抗菌药剂(如叶枯唑、噻菌铜、可杀得等)防效低、抗性强，急需发现高效抗植病细菌的活性化合物，在此基础上创制出自主知识产权的绿色新农药，为农作物细菌性和病毒性病害防控提供候选药物。
而含噻唑盐的衍生物表现出了广谱的生物活性，如在杀菌方面具有抗革兰氏阳性(或阴性)菌等生物活性，成为化学界和生物学界学者们关注的热点。与传统的季铵盐阳离子相比，噻唑盐阳离子具有很好的平面性、电子容易转移、离域性好等特点，容易与受体发生作用，并且其合成简单、成本低廉，能扰乱微生物细胞膜本有的防御机制，因此具有广泛的生物活性。同时，含1,3,4-噁二唑基团的化合物被广泛合成和研究，已报道这类化合物具有广谱的生物活性(如杀菌、杀虫、除草、抗炎等)。
为了寻找和发现高效杀菌剂，本发明以含1,3,4-噁二唑基团的衍生物为基础，将能够提高目标化合物生物活性的噻唑盐基团引入到此体系中，合成一系列含1,3,4-噁二唑基团的噻唑盐类化合物，测试其抗植病细菌活性，为新农药的研发和创制提供科学基础。
具有生物活性的1,3,4-噁二唑类化合物研究进展：
2011年，Xu[Xu,W.M.；Yang,S.；Bhadury,P.；He,J.；He,M.；Gao,L.L.；Hu,D.Y.；Song,B.A.Synthesis and bioactivity of novel sulfone derivatives containing 2,4-dichlorophenyl substituted 1,3,4-oxadiazole/thiadiazole moiety as chitinaseinhibitors.Pestic.Biochem.Physiol.,2011,11,6-15]合成了含1,3,4-噁二唑基团的硫醚或砜类衍生物作为几丁质酶抑制剂，生物活性测试结果表明，该类化合物具有良好的抗真菌活性。其中，化合物17a,17b,17c在50μg/mL浓度下对小麦赤霉病菌的抑制率分别85.1％,100.0％,79.9％，均高于对照药剂恶霉灵抑制率(60.7％)，进一步的实验结果表明化合物15b能作为几丁质酶抑制剂用于植物真菌性病害的防控。
2013年，Li等[Li,P.；Yin,J.；Xu,W.M.；Wu,J.；He,M.；Hu,D.Y.；Yang,S.；Song,B.A.Synthesis,antibacterial activities,and 3D-QSAR of sulfone derivativescontaining 1,3,4-oxadiazole moiety.Chem.Biol.Drug.Des.；2013；82,546–556]合成一系列含1,3,4-噁二唑基团的砜类化合物，抑菌活性测试结果表明，该类化合物对番茄和烟草青枯病菌表现出较好的抑制活性。其中，化合物22a和22b对番茄和烟草青枯病菌表现出最好的抑制活性，EC50分别为19.77和8.29μg/mL，优于对照药剂可杀得3000和噻菌酮(两者对番茄青枯病菌的EC50分别为93.59和99.80μg/mL，对烟草青枯病菌的EC50分别为45.91和216.70μg/mL)。
2016年，Wang等[Wang,P.Y.；Zhou,L.；Zhou,J.；Wu,Z.B.；Xue,W.；Song,B.A.；Yang,S.Synthesis and antibacterial activity of pyridinium-tailored 2,5-substituted-1,3,4-oxadiazole thioether/sulfoxide/sulfone derivatives.Bioorg.Med.Chem.Lett.,2016,26,1214-1217]设计并合成了一系列含吡啶盐的1,3,4-噁二唑硫醚/亚砜/砜类化合物，并对该类化合物进行抑菌活性测试，生物活性测试结果表明该系列化合物对植物致病细菌具有很好的抑制作用，其中化合物26a，26b，26c，246，26e，26f，26g对水稻白叶枯病菌、烟草青枯病菌、柑橘溃疡病菌表现出显著的抑制活性，其EC50值的范围为0.54～12.14μg/mL，远高于对照药剂叶枯唑对水稻白叶枯病菌的EC50(92.61μg/mL)及噻菌酮对烟草青枯病菌与柑橘溃疡病菌的EC50(分别为216.7μg/mL和77.04μg/mL)。
2016年，Shi等[Shi,Y.J.；Li,Y.；Fang,Y.；Chen,J.；Ye,L.Y.；Ge,S.S.；Dai,H.Synthesis and biological activities of novel cyanoacrylates containing 1,3,4-oxadiazole moiety.Chin.J.Org.Chem.,2016,36,2472-2478]通过活性亚结构拼接方法，合成了一系列含1,3,4-噁二唑环的氰基丙烯酸酯类化合物，初步的生物活性测试结果表明该类化合物具有一定的除草活性，在1500g/ha剂量下，化合物28a对繁缕的茎叶处理抑制率为80％，化合物28b对小藜的茎叶处理抑制率为70％。
具有广谱生物活性的噻唑盐类化合物研究进展：
1999年，Maeda等[Maeda,T.；Yoshida,M.；Okazaki,K.；Nagamune,H.；Kourai,H.Synthesis and Antimicrobial Characteristics of 5,5'-[2,2'-(Tetramethylenedicarbonyldioxy)diethyl]bis(3-alkyl-4-methylthiazoliumiodide).Biocontrol.Sci.Lett.,1999,4,75-81]合成了一组不同烷基链长的对称T-n二聚体的噻唑盐—双子季铵盐。生物活性测定结果表明，化合物30具有广谱、高效的杀细菌和真菌活性，当链长为12个碳时，活性最好，且效果均优于商品药十二烷基二甲基苄基氯化铵和噻菌灵。
2015年，Zablotskaya等[Zablotskaya,A.；Segal,I.；Geronikaki,A.；Kazachonokh,G.；Popelis,Y.；Shestakova,I.Synthesis and biological evaluation oflipid-like 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole derivatives as potentialanticancer and antimicrobial agents.Med.Chem.Commun.,2015,6,1464-1470]合成了不同取代的噻唑盐类化合物，并在体外测试其抗肿瘤和抗菌活性。生物活性测试结果表明，其中化合物33a和33b对Gram-(+)表现出很强的抗菌活性，其中，对金黄色葡萄球菌的最小抑制浓度<2μg/mL，最小杀菌浓度为4μg/mL。构效关系表明，这类化合物的活性取决于烷基链的长度、烷基化的位置、烷基的数量。
2015年，Tejero等[Tejero,R.；López,D.；López-Fabal,F.；Gómez-Garcés,J.；Fernández-García,M.High Efficiency Antimicrobial Thiazolium and TriazoliumSide-Chain Polymethacrylates Obtained by Controlled Alkylation of theCorresponding Azole Derivatives.biomacromolecules,2015,16,1844-1854]合成了2种聚合物34a和34b，并研究其季铵化反应程度(DQs)对抗菌活性的影响。活性测试表明，在季铵化达到100％时，两者表现出明显的抗菌活性，其MIC值分别为8μg/mL和4μg/mL。
发明内容
本发明的目的是：提供一种含1,3,4-噁二唑基的噻唑盐类化合物及其制备方法及应用，它对致病病原细菌具有良好的抑制效果，且其合成方法经济简便。
本发明是这样实现的：一种含1,3,4-噁二唑基的噻唑盐类化合物，该化合物具有如通式(Ⅰ)所示的结构：
式中，苯环上的取代基为一个以上，R1为氢、C1-4烷基、三氟甲基、C1-3烷氧基、三氟甲氧基、羟基、丙烯基、丙烯酰胺基、氨基、C1-3烷氨基、硝基或卤素原子；R2为氢、C1-4烷基、三氟甲基、C1-3烷氧基、硝基或卤素原子；X为氧原子或硫原子；n1为0,1,2或3；n2为大于1的自然数。
含1,3,4-噁二唑基的噻唑盐类化合物的制备方法，其特征在于：其合成路线如下；
式中，R1为氢、C1-4烷基、三氟甲基、C1-3烷氧基、三氟甲氧基、羟基、丙烯基、丙烯酰胺基、氨基、C1-3烷氨基、硝基或卤素原子；R2为氢、C1-4烷基、三氟甲基、C1-3烷氧基、硝基或卤素原子；X为氧原子或硫原子；n1为0,1,2或3；n2为大于1的自然数。
含1,3,4-噁二唑基的噻唑盐类化合物在制备抗致病病原细菌的药物中的应用。
通过采用上述技术方案，本发明以含1,3,4-噁二唑基团的衍生物为基础，将能够改善目标化合物生物活性的噻唑盐阳离子引入到此体系中，合成一系列含1,3,4-噁二唑基的噻唑盐类化合物，通过对植物致病细菌的生物活性测试，发现该类化合物对测定的植物致病病原细菌(如水稻白叶枯病菌、烟草青枯病菌和柑橘溃疡病菌等)具有良好的抑制作用，为研发和创制新农药提供了一定的科学参考。
具体实施方式
本发明的实施例1：目标化合物6-(5-(2,4-二氯苯基)-己硫醚基)-1,3,4-噁二唑-3-溴化噻唑盐的制备
在25mL圆底烧瓶中加入0.68g(1.66mmol)2-(6-溴己硫醚基)-5-(2,4-二氯苯基)-1,3,4-噁二唑，并用5mL乙腈溶解，接着加入710μL噻唑液体，加热回流，反应36h左右，TLC检测反应原料基本反应完全，停止反应，减压蒸馏除去溶剂乙腈，加入少量无水甲醇溶解，硅胶拌样，柱层析(二氯甲烷:无水甲醇＝6:1,V/V)分离纯化得目标产物0.62g，产率75.9％，熔点：118～120℃。
其它目标化合物的合成参照实施例1。
合成的部分含1,3,4-噁二唑基的噻唑盐类化合物的结构及核磁共振氢谱和碳谱数据如表1所示，物化性质如表2所示。
表1 部分化合物的核磁共振氢谱和碳谱数据
表2 部分目标化合物的理化性质
药理实施例1：
EC50(median effective concentration)是评估植物病原菌对化合物敏感性的重要指标，同时也是在研究化合物的作用机制时，化合物浓度设置的重要参数。在浓度梯度实验中，采用二倍稀释法设定合适的5个浓度，最后将药剂对植物病原菌的抑制率、药剂浓度换算成对数值，通过SPSS软件回归分析得到毒力曲线，计算出EC50。
采用浊度法测试目标化合物对植物病原菌的有效中浓度EC50，试验对象为水稻白叶枯病菌、烟草青枯病菌和柑橘溃疡病菌。DMSO溶解在培养基中作为空白对照。将水稻白叶枯病菌(水稻白叶枯病原菌在M210固体培养基)放到NB培养基中，在28℃、180rpm恒温摇床中振荡培养到对数生长期备用；烟草青枯病原菌在NA固体培养基上进行划线培养，放置在30℃恒温培养箱中，直到长出单菌落，挑取单菌落，将烟草青枯病菌放到NB液体培养基，在30℃、180rpm恒温摇床中振荡培养到对数生长期备用；将柑橘溃疡病菌(在M210固体培养基上)放到NB培养基中，在28℃、180rpm恒温摇床中振荡培养到对数生长期备用。将药剂(化合物)配置成不同浓度(例：80,40,20,10,5μg/mL)的含毒NB液体培养基5mL加入到试管中，分别加入40μL含有植病细菌的NB液体培养基，在28-30℃、180rpm恒温摇床中振荡，其水稻白叶枯病原菌培养48h，烟草青枯病菌培养24h，柑橘溃疡病菌培养36h。将各个浓度的菌液在分光光度计上测定OD595值，并且另外测定对应浓度的含毒无菌NB液体培养基的OD595值。
校正OD值＝含菌培养基OD值－无菌培养基OD值
抑制率％＝[(校正后对照培养基菌液OD值－校正含毒培养基OD值)/校正后对照培养基菌液OD值]×100
本发明实施例辅以说明本发明的技术方案，但实施例的内容并不局限于此，部分目标化合物实验结果如表3所示。
表3 含1,3,4-噁二唑基的噻唑盐类化合物对植物病原细菌的抑制活性
“NT”表示未测试
从表3中可以看出，在体外生物活性测试中，目标化合物对植物致病病原菌(如水稻白叶枯病菌、烟草青枯病菌以及柑橘溃疡病菌)表现出了较好的抑制活性。值得一提的是，目标化合物对水稻白叶枯病菌表现出相对优良的抑制活性，其EC50在0.10～10.56μg/mL范围内，其中，化合物47的抑制活性最好，其EC50为0.10μg/mL。化合物对柑橘溃疡病菌也表现出较好的抑制活性，其EC50在2.34～17.58μg/mL范围内，其中，化合物13的抑制效果最佳，其EC50为2.34μg/mL。而针对烟草青枯病菌抑制活性的EC50值在3.27～85.27μg/mL范围内，其中，活性最好的化合物是30，其EC50为3.27μg/mL。对3种植病细菌的整体抑制效果来说，目标化合物12，16，30，32，36，40，46，47和48对3种植病细菌表现出广谱抑制效果，其EC50在0.10～14.59μg/mL之间。可见，本发明的化合物可作为抗植物病原细菌的候选农药。
Claims (4)
1.一种含1,3,4-噁二唑基的噻唑盐类化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
式中，R1为氢、C1-4烷基、三氟甲基、C1-3烷氧基、三氟甲氧基、羟基、氨基、C1-3烷氨基、硝基或卤素原子；R2为氢、C1-4烷基、三氟甲基、C1-3烷氧基、硝基或卤素原子；X为氧原子或硫原子；n1为0,1,2或3；n2为大于1的自然数。
2. 一种含1,3,4-噁二唑基的噻唑盐类化合物，其特征在于选自下述具体化合物：
。
3.一种如权利要求1或2所述的含1,3,4-噁二唑基的噻唑盐类化合物的制备方法，其特征在于：其合成路线如下：
式中，R1为氢、C1-4烷基、三氟甲基、C1-3烷氧基、三氟甲氧基、羟基、氨基、C1-3烷氨基、硝基或卤素原子；R2为氢、C1-4烷基、三氟甲基、C1-3烷氧基、硝基或卤素原子；X为氧原
子或硫原子；n1为0,1,2或3；n2为大于1的自然数。
4.如权利要求1或2所述的含1,3,4-噁二唑基的噻唑盐类化合物在制备抗水稻白叶枯病菌药物的应用。
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