CN106922679A - 吩嗪‑1‑甲酰胺改造化合物15‑1在抑制油菜菌核病菌中的应用 - Google Patents
吩嗪‑1‑甲酰胺改造化合物15‑1在抑制油菜菌核病菌中的应用 Download PDFInfo
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Abstract
一种吩嗪‑1‑甲酰胺改造化合物15‑1在抑制油菜菌核病菌中的应用，该吩嗪‑1‑甲酰胺改造化合物15‑1是以吩嗪‑1‑甲酰胺为母体，经结构改造获得。本发明同时采用生长速率法测定了该吩嗪‑1‑甲酰胺改造化合物15‑1对油菜菌核病菌的抑制作用，结果显示：该改造化合物15‑1对油菜菌核病菌具有较好的抑制效果好，且该抑制效果强于其母体吩嗪‑1‑甲酰胺，表明该改造化合物15‑1可作为防控油菜菌核病新农药的先导化合物。
Description
技术领域
本发明属于农药创制领域，特别涉及吩嗪-1-甲酰胺改造化合物15-1在抑制油菜菌核病菌(Sclerotinia sclerotiorum)中的应用。
背景技术
油菜是我国重要的油料作物，种子含油量介于33-55％，具有较高的经济价值。油菜不仅可以用来榨取食用油和饲料，而且还在医药、工业、食品等方面具有广泛的用途。最近的研究结果表明，我国是世界上油菜种植大国，其面积约为七百万公顷，是重要的油菜生产国。
油菜的生长周期长，常受各种因素的干扰，其中油菜菌核病是影响油菜增产的重要因素。该病又称为茎腐病、霉蔸、白秆、空秆等，是一种由核盘菌引起的真菌性病害，可寄生于70多科400多种植物。该病的寄主除十字花科植物外，还可寄生在花生、蚕豆、向日葵、莴苣等作物上。菌核的存在是引起油菜菌核病的初侵染源。菌核萌发后产生的子囊孢子在空气中传播，子囊孢子一般首先落到植株的花瓣上侵染花瓣，然后通过感染病菌的花瓣落到植株的茎叶上侵染植株。该病的发生会引起油菜千粒重降低、角果减少、种子皱瘪、植株早枯等，导致油菜减产10％-50％，甚至达80％，给生产上带来巨大损失。
生产上防治油菜菌核病的方法主要依赖化学防治，可用于控制油菜菌核病的化学农药有麦角甾醇生物合成抑制剂类如咪酰胺、戊唑醇；苯并咪唑类如多菌灵、甲基托布津；取代苯类如百菌清；二甲酰亚胺类如菌核净、腐霉利、异菌脲、乙烯菌核利；三唑类如丙环唑；氨基甲酸酯类如乙霉威等，但长期大量单一使用化学农药，不仅污染环境，破坏生态平衡，而且还容易导致病菌产生抗药性。因此，探寻防治油菜菌核病的新农药刻不容缓。
目前，开发新农药的途径主要有化学合成、已有化合物的结构改造、从植物或微生物体内筛选结构新颖的化合物等，其中已有化合物的结构改造是开发新农药的方法，不仅可以节约研发成本，而且短期效益显著。本课题组曾研究了吩嗪-1-甲酰胺，但其抑制作用有限，因此，本课题组以吩嗪-1-甲酰胺为母体，通过结构改造并获得了吩嗪-1-甲酰胺改造化合物15-1。为明确该改造物的开发潜力，本发明评价了其对油菜菌核病菌的抑制效果及增效作用，旨在为丰富防治油菜菌核病的新农药提供理论依据和实践基础。
发明内容
本发明所要解决的技术问题是，提供一种吩嗪-1-甲酰胺改造化合物15-1在抑制油菜菌核病菌中的应用，该改造化合物15-1是以吩嗪-1-甲酰胺为母体经结构改造获得，采用菌丝生长速率法评价该改造化合物15-1对油菜菌核病菌的抑制效果，结果表明该改造化合物15-1对油菜菌核病菌的抑制效果好，且该抑制效果强于其母体吩嗪-1-甲酰胺。
为解决上述技术问题，本发明所采用的技术方案是：一种吩嗪-1-甲酰胺改造化合物15-1在抑制油菜菌核病菌中的应用。
本发明同时提供一种吩嗪-1-甲酰胺改造化合物15-1在制备防控油菜菌核病农药中的应用
上述吩嗪-1-甲酰胺改造化合物15-1的结构式如下：
上述吩嗪-1-甲酰胺改造化合物15-1是以吩嗪-1-甲酰胺为母体，将其在酸性条件下水解生成吩嗪-1-羧酸；再以吩嗪-1-羧酸和亚硫酰氯进行回流反应获得中间产物吩嗪-1-甲酰氯；最后将吩嗪-1-甲酰氯溶于干燥二氯甲烷，置于冰水浴中冷却，0℃条件下先后加入三乙胺和3-甲氧基-1-丙胺，于室温下反应制得。
与现有技术相比，本发明具有的优点为：本改造化合物15-1对油菜菌核病菌具有较强的毒力，其EC50为4.25μg/mL，比对照药剂(母体吩嗪-1-甲酰胺)的EC50低；本改造化合物15-1对油菜菌核病菌的抑制效果好，且强于其母体，并不易使病菌产生抗药性，丰富了防治油菜菌核病菌的新农药。
附图说明
图1是本发明改造化合物15-1的质谱图。
具体实施方式
下面结合具体试验和实施例对本发明的技术方案作进一步说明，本发明试验和实施例中涉及的百分比均为质量百分比。
实施例1 吩嗪-1-甲酰胺改造化合物15-1的制备
合成的具体过程：将吩嗪-1-甲酰胺在酸性条件下水解生成吩嗪-1-羧酸；取20mmol吩嗪-1-羧酸(0.4577g)和200ml亚硫酰氯加入到500ml圆底烧瓶中，安装回流反应装置(使用无水氯化钙干燥管)，磁力搅拌，回流反应6h，反应液冷却后旋蒸移除亚硫酰氯，获得中间产物吩嗪-1-甲酰氯，不需纯化直接用于下一步反应；将获得的吩嗪-1-甲酰氯溶于200ml干燥二氯甲烷(DCM)，加入到500ml干燥圆底烧瓶中，氮气保护，磁力搅拌，置于冰水浴中冷却，0℃条件下先后加入11.15ml三乙胺(80mmol，4equiv.)和2.367g 3-甲氧基-1-丙胺(20mmol，1equiv.)，加料完毕后撤除冰水浴，室温条件下反应14h，间歇取样，TLC监测反应，旋蒸移除DCM后萃取三次，每次使用450ml液体(乙酸乙酯与H2O按2:1的体积比混合)萃取，合并有机相，使用无水硫酸钠干燥12h，过滤，使用EA洗涤固体硫酸钠，旋蒸，得改造化合物产品15-1，1.4833g，产率22.93％。
实施例2 改造化合物15-1的结构鉴定
采用核磁共振氢谱(1H NMR)，核磁共振碳谱(13C NMR)技术对获得的改造化合物15-1进行测定。经氢谱(1H NMR(500MHz,CDCl3)δ11.03(s,12H),9.25–8.90(m,59H),8.90–7.86(m,427H),8.11–7.73(m,224H),8.11–7.73(m,223H),7.82(dd,J＝16.5,10.4Hz,19H),7.29(s,16H),7.10–6.85(m,6H),5.86–5.75(m,8H),5.33–5.23(m,9H),4.82(t,J＝9.7Hz,9H),4.89–4.39(m,14H),4.89–4.24(m,19H),4.89–4.18(m,23H),4.89–4.07(m,29H),4.89–4.02(m,32H),4.89–3.71(m,81H),3.68(d,J＝20.8Hz,17H),3.71–3.51(m,22H),3.71–3.30(m,38H),3.71–3.26(m,43H),3.71–3.20(m,53H),3.71–3.03(m,80H),3.71–3.05(m,80H),3.71–2.93(m,83H),3.71–2.88(m,84H),3.71–2.81(m,85H),3.71–2.45(m,128H),3.71–2.41(m,133H),3.71–2.27(m,150H),3.71–2.17(m,155H),3.71–2.12(m,159H),3.71–2.07(m,169H),3.71–2.01(m,175H),3.71–1.70(m,258H),3.71–1.62(m,273H),3.71–1.54(m,292H),3.71–1.40(m,351H),1.24(dd,J＝37.1,31.7Hz,182H),1.04(t,J＝6.9Hz,19H),0.92(dd,J＝41.2,7.3Hz,48H),0.18–-0.07(m,161H).)、碳谱(13C NMR(126MHz,CDCl3)δ165.89(s),143.98(s),143.26(s),142.68(s),139.95(s),139.75(s),137.35(s),135.44(s),135.02(s),133.48(s),133.17(s),131.73(d,J＝9.5Hz),131.12(s),130.58(s),130.32–129.88(m),129.80–129.54(m),129.45(s),128.99(s),127.89(s),124.85(s),77.26(s),77.00(s),76.75(s),46.33(s),39.50(s),39.14(s),33.58(s),28.91(s),22.52(s),14.00(s),0.96(s).)结合质谱(分子量：323.20，图1)检测合成的化合物与预期目标吻合，其分子式为C18H17N3O3，结构式如下：
实施例3 改造化合物15-1对草莓灰霉病菌的抑制作用
⑴仪器及相关材料
YJ-VS-2型超净工作台(无锡一净净化设备有限公司)，LDZX-30E灭菌锅(上海申安医疗器械厂)，MPJ-250型培养箱(上海森信实验仪器有限公司)，QHX-400B-III型光照培养箱(上海新苗医疗器械制造有限公司)，电炉(北京中兴伟业仪器有限公司)等以及量筒、玻璃棒、烧杯、三角瓶、直尺、铅笔、标签纸、封口膜、挑针、容量瓶、接种针、ph-101喷壶、打孔器、培养皿、菜刀、纱布。
⑵药剂
实施例1制备得到的93％吩嗪-1-甲酰胺改造物15-1原药(以下简称改造物15-1)；琼脂、葡萄糖、丙酮和吐温80等药剂均从国药集团购买。
⑶菌株
试验用野生敏感型的油菜菌核病菌(Sclerotinia sclerotiorum)由湖南农业大学植物病理实验室分离、鉴定和保存。
⑷改造物15-1对油菜菌核病菌的活性测定方法
采用生长速率法测定改造物15-1对油菜菌核病菌(Sclerotinia sclerotiorum)的抑菌作用。取适量丙酮将改造物15-1原药溶解后配制成质量浓度为1000μg/mL的母液，按药液与培养基1：9的体积比配制成最终含药量为2.5、5、10、20、40μg/mL的含药平板，用直径5mm的打孔器在预培养2d的油菜菌核病菌菌落边缘打取菌饼正面朝下接种到含药平板上，每处理重复3次，以无药平板作空白对照，置于26-28℃培养箱中，待对照菌落直径长至整个培养的2/3时，采用十字交叉法测量各处理的菌落直径。同时，采用同样的方法测试吩嗪-1-甲酰胺对油菜菌核病菌的抑制作用。计算抑制率，EC50值，相关系数及回归方程。
⑸结果与分析
由表1可知，改造物15-1浓度越高，抑菌效果越好。当改造物15-1浓度为40μg/mL时，抑菌效果最好，其抑制率为94.68％；改造物15-1浓度为20μg/mL时，抑菌效果次之；其他处理的抑制率低于90％。该药剂对油菜菌核病菌具有较强毒力效果(EC50为0.37μg/mL，回归方程为Y＝0.7857x+5.3393，相关系数为0.9890)，其毒力强于对照药剂吩嗪-1-甲酰胺(EC50为14.31μg/mL，回归方程为Y＝1.2266x+3.6858，相关系数为0.9132)，抑制率明显高于对照药剂吩嗪-1-甲酰胺(见表2)，说明改造物15-1可作为防控油菜菌核病新农药的先导化合物。
表1吩嗪-1-甲酰胺改造物15-1对油菜菌核病菌的抑制作用
表2吩嗪-1-甲酰胺(对照药剂)对油菜菌核病菌的抑制作用
Claims (4)
1.一种吩嗪-1-甲酰胺改造化合物15-1在抑制油菜菌核病菌中的应用。
2.一种吩嗪-1-甲酰胺改造化合物15-1在制备防控油菜菌核病农药中的应用。
3.如权利要求1或2所述的应用，其特征在于，所述吩嗪-1-甲酰胺改造化合物15-1的结构式如下：
4.如权利要求3所述的应用，其特征在于，所述吩嗪-1-甲酰胺改造化合物15-1是以吩嗪-1-甲酰胺为母体，将其在酸性条件下水解生成吩嗪-1-羧酸；再以吩嗪-1-羧酸和亚硫酰氯进行回流反应获得中间产物吩嗪-1-甲酰氯；最后将吩嗪-1-甲酰氯溶于干燥二氯甲烷，置于冰水浴中冷却，0℃条件下先后加入三乙胺和3-甲氧基-1-丙胺，于室温下反应制得。
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