新型1, 3, 4-噻二唑并[3, 2-<i>a</i>]嘧啶酮类介离子衍生物的合成及其生物活性

引用本文: 何文静, 刘登曰, 甘秀海, 张建, 刘峥军, 易崇粉, 宋宝安. 新型1, 3, 4-噻二唑并[3, 2-a]嘧啶酮类介离子衍生物的合成及其生物活性[J]. 有机化学, 2019, 39(8): 2287-2294. doi: 10.6023/cjoc201903023 shu

Citation: He Wenjing, Liu Denyue, Gan Xiuhai, Zhang Jian, Liu Zhengjun, Yi Chongfen, Song Bao'an. Synthesis and Biological Activity of Novel 1, 3, 4-Thiadiazolo[3, 2-a]pyrimidinone Mesoionic Derivatives[J]. Chinese Journal of Organic Chemistry, 2019, 39(8): 2287-2294. doi: 10.6023/cjoc201903023 shu

新型1, 3, 4-噻二唑并[3, 2-a]嘧啶酮类介离子衍生物的合成及其生物活性

贵州大学绿色农药与农业生物工程国家重点实验室培育基地/教育部绿色农药与生物工程重点实验室/精细化工研究开发中心贵阳 55002

通讯作者: 宋宝安, songbaoan22@yahoo.com

基金项目:

国家重点研发计划(No.2018YFD0200100)资助项目

摘要: 以三氟苯嘧啶为先导化合物，设计并合成了一系列结构新颖的1，3，4-噻二唑并[3，2-a]嘧啶酮类介离子衍生物.利用¹H NMR，¹³C NMR，¹⁹F NMR和HRMS对其进行结构表征.初步生物活性表明，多数化合物在100 μg/mL浓度下表现出一定的杀虫活性，其中2-（（4-溴苄基）硫基）-8-（（2-氯噻唑-5-基）甲基）-5-氧代-6-（3-（三氟甲基）苯基）-5H-[1, 3, 4]噻二唑并[3，2-a]嘧啶-8-鎓-7-盐（8b）和2-（（（2-氯噻唑-5-基）甲基）硫基）-8-（（2-氯噻唑-5-基）甲基）-5-氧代-6-（3-（三氟甲基）苯基）-5H-[1, 3, 4]噻二唑并[3，2-a]嘧啶-8-鎓-7-盐（8d）对白背飞虱（white-backed planthopper，WBPH）的致死率均为70%；此外，部分化合物在浓度为50 μg/mL时对水稻白叶枯病菌（Xanthomonas oryzae pv. oryzae，Xoo），水稻细菌性条斑病菌（Xanthomonas oryzae pv. oryzicola，Xoc）和柑橘溃疡病菌（Xanthomonas citri pv. citri，Xcc）表现出较好的抑抗菌性，其中2-（（2-（三氟甲基）苄基）硫基）-8-（（2-氯噻唑-5-基）甲基）-5-氧代-6-（3-（三氟甲基）苯基）-5H-[1, 3, 4]噻二唑并[3，2-a]嘧啶-8-鎓-7-盐（8h）对水稻白叶枯病菌和水稻细菌性条斑病菌的抑制率分别为70.91%和53.34%，均优于对照药剂三氟苯嘧啶（42.85%和51.22%）、噻菌铜（47.76%和23.25%）和叶枯唑（66.97%和17.24%）；2-（（3-（三氟甲基）苄基）硫基）-8-（（2-氯噻唑-5-基）甲基）-5-氧代-6-（3-（三氟甲基）苯基）-5H-[1, 3, 4]噻二唑并[3，2-a]嘧啶-8-鎓-7-盐（8e）对柑橘溃疡病菌的抑制率为68.97%，优于噻菌铜（35.85%）和叶枯唑（37.53%）.

关键词:

English

Synthesis and Biological Activity of Novel 1, 3, 4-Thiadiazolo[3, 2-a]pyrimidinone Mesoionic Derivatives

State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025

Corresponding author: Song, Bao'an, E-mail: songbaoan22@yahoo.com

Received Date: 13 March 2019
Revised Date: 05 April 2019
Available Online: 25 August 2019
Fund Project:

Project supported by the National Key Research and Development Program of China (No. 2018YFD0200100)

Abstract: A series of 1, 3, 4-thiadiazolo[3, 2-a]pyrimidinone mesoionic derivatives were designed and synthesized with triflumezopyrim as the leading compound, and their structures were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The preliminary biological activities indicated that the target compounds showed certain insecticidal activities at 100 μg/mL, of which the lethality rates of 2-((4-chlorobenzyl)thio)-8-((2-chlorothiazol-5-yl)methyl)-5-oxo-6-(3-(trifluoromethyl)phen-yl)-5H-[1, 3, 4]-thiadiazolo[3, 2-a]pyrimidin-8-ium-7-olate (8b) and 2-(((2-chlorothiazol-5-yl)methyl)thio)-8-((2-chlorothiazol-5-yl)methyl)-5-oxo-6-(3-(trifluoromethyl)phenyl)-5H-[1, 3, 4]thiadiazolo-[3, 2-a]pyrimidin-8-ium-7-olate (8d) against white-backed planthopper (WBPH) were 70%. Some compounds showed good antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc) and Xanthomonas citri pv. citri (Xcc) at 50 μg/mL, and the inhi-bitory rates of 2-((2-(trifluoromethyl)benzyl)thio)-8-((2-chlorothiazol-5-yl)methyl)-5-oxo-6-(3-(trifluoromethyl)phenyl)-5H-[1, 3, 4]thiadiazolo[3, 2-a]pyrimidin-8-ium-7-olate (8h) to Xoo and Xoc were 70.91% and 53.34%, respectively, which were better than thiodiazole copper (47.76% and 23.25%) and bismerthiazol (66.97% and 17.24%). The inhibition rate of 2-((3-(tri-fluoromethyl)benzyl)thio)-8-((2-chlorothiazol-5-yl)methyl)-5-oxo-6-(3-(trifluoromethyl)phenyl)-5H-[1, 3, 4]thiadiazolo[3, 2-a]-pyrimidin-8-ium-7-olate (8e) to Xcc was 68.97%, which was better than thiediazole copper (35.85%) and bismerthiazol (37.53%)

Key words:

mesoionic
/ 1, 3, 4-thiadiazolo[3, 2-a]pyrimidinone
/ insecticidal activity
/ antibacterial activity

1935年, Earl等^[1]在用乙酸酐处理由N-苯基甘氨酸与亚硝酸反应得到的N-亚硝基-N-苯基甘氨酸时, 意外得到一种稳定的晶体化合物, 该化合物在酸性和碱性条件下均可水解, 将其命名为悉尼酮^[2].其结构是由成环的各个原子供给π电子而组成离域的6电子体系, 难以用一般的价键结构来表示^[3].因此, 引入了介离子化合物(mesoionic compounds)的概念来表示悉尼酮及其类似物与一般内盐或两性离子化合物的区别^[4].由于介离子环内所带正电荷与环外共价键连接的原子或原子团所带的负电荷平衡, 因此易于进行各种亲电取代反应^[5].该类化合物也可作为环状偶极体, 与炔烃^[6]和烯烃^[7]发生1, 3-偶极环加成反应.介离子环状偶极体结构和反应特性, 激起了人们对这类化合物及其偶极环加成反应更浓厚的兴趣.

介离子化合物除了具有较优的结构和反应特性之外, 还因具有抗真菌^[8]、抗细菌^[9~11]、抗炎^[12]、抗肿瘤^[13]和杀虫^[14~16]等多种生物活性而倍受药物学家们的关注.在农药领域, 杜邦公司已研发出三氟苯嘧啶(Triflume- zopyrim, TFM)^[17]和Dicloromezotiaz(图 1)^[18]两种介离子杀虫剂, 研究表明这类新型介离子杀虫剂作为烟碱乙酰胆碱受体抑制剂与新烟碱类杀虫剂无交互抗性^[19].目前对此类介离子化合物的结构修饰主要集中在对介离子吡啶并[1, 2-a]嘧啶酮环的改造和1-位及3-位上的基团修饰^[20~24], 但仅有少数化合物在500 μg/mL的浓度下对褐飞虱的防效超过75%. 2016年, 日本化药株式会社专利^[25]公开了一类在1-位引入氰基乙基结构的介离子化合物, 其中多数化合物对棉蚜和褐飞虱表现出优异的杀虫活性. 2018年, 本课题组^[26]前期报道了在1-位引入新烟碱活性结构的吡啶并[1, 2-α]嘧啶酮类介离子化合物, 活性结果表明部分化合物表现出一定的杀虫和抗菌活性, 但未能发现对白背飞虱具有较好致死效果的化合物.

图 1

图 1. 目标化合物的设计思路

Figure 1. Design strategy of target compounds

下载: 全尺寸图片幻灯片

近年来, 杂环类结构被广泛应用于新农药的创制, 其中1, 3, 4-噻二唑是一类典型的杂环结构, 具有杀虫^{[27, 28]}、抑菌^[29]、抗病毒^[30]和除草^[31]等多种生物活性.特别是含1, 3, 4-噻二唑骨架的硫醚类衍生物结构作为一类重要的药效团片段^{[32, 33]}, 存在于多种药物分子结构中.为了寻求具有较高杀虫和抗菌活性的介离子类药物分子, 在前期研究基础上, 本工作以商品药剂TFM为先导化合物, 在保留三氟甲基苯基的前提下, 将5-氨基- 1, 3, 4-噻二唑-2-硫醇结构与丙二酸酯单元杂化构建1, 3, 4-噻二唑并[3, 2-a]嘧啶母环; 同时, 以dicloromezotiaz的噻唑杂环代替TFM中1位的嘧啶环, 设计合成了一系列1, 3, 4-噻二唑并[3, 2-a]嘧啶类介离子化合物(图 1), 并评价它们的杀虫及抑菌活性.目标化合物的合成路线见Scheme 1.

图式 1

图式 1. 目标化合物8a~8n的合成路线

Scheme 1. Synthetic routes of target compounds 8a~8n

下载: 全尺寸图片幻灯片

1. 结果与讨论

1.1 化合物的合成

如Scheme 1所示, 首先以间三氟甲基苯乙酸为原料, 浓硫酸作催化剂, 通过酯化反应得到中间体1.之后中间体1、碳酸二甲酯在NaH条件下通过Claisen酯缩合反应得到中间体2, 然后进行水解, 得到中间体3, 最后再与2, 4, 6-三氯苯酚缩合得到中间体4.与此同时, 不同取代卤代烃与5-氨基-1, 3, 4-噻二唑-2-硫醇进行亲核取代反应得到中间体5a~5n, 之后甲酰化得到中间体6a~6n, 再与2-氯-5-(氯甲基)-噻唑发生亲核取代反应得到中间体7a~7n, 最终以甲苯为溶剂, 与中间体4回流缩合得到目标化合物8a~8n.

1.2 化合物波谱分析

所合成目标化合物均通过¹H NMR, ¹³C NMR, ¹⁹F NMR和HRMS确定结构.以目标化合物8a为例, 在¹H NMR中, δ 7.45~8.07处出现的多重峰为苯环上的氢的吸收信号, 噻唑上的氢周围没有氢的存在, 表现为s峰, 化学位移δ为7.80, 在δ 5.36出现的s峰为S-CH₂-Ar氢的吸收信号, 在高场位置δ: 4.51归属于介离子环上与噻唑连接的亚甲基上的氢.在¹³C NMR中153.0, 136.4和136.0出现的峰为噻唑上的三个碳的吸收峰, δ为161.2, 154.2的峰为噻二唑上的碳原子, 相应的介离子环上的碳原子化学位移值出现在158.1, 157.5, 142.9.在¹⁹F NMR中, δ为－60.9也验证了三氟苯基的存在.在HRMS谱图中, 目标产物的HRMS [M+H]⁺实测值和理论计算值一致, 误差均在δ 3以内. EI-MS结果也显示出了相应碎片离子峰的信息, 这进一步证实了目标化合物的结构.

1.3 生物活性测试结果

表 1列出了目标化合物8a~8n对白背飞虱(white- backed planthopper, WBPH), 水稻白叶枯病菌(Xantho-monas oryzae pv. oryzae, Xoo), 水稻细菌性条斑病菌(Xanthomonas oryzae pv. oryzicola, Xoc)和柑橘溃疡病菌(Xanthomonas citri pv. citri, Xcc)的生物活性测试结果. 结果表明在浓度为100 μg/mL时大多数化合物对白背飞虱表现出一定的致死率, 化合物8b和8d对白背飞虱的致死率为70%.在浓度为50 μg/mL时, 目标化合物对水稻白叶枯病菌、水稻细菌性条斑病菌和柑橘溃疡病菌三种细菌表现出较好的抑制作用.其中化合物8h对水稻白叶枯病菌和水稻细菌性条斑病菌的抑制率分别为70.91%和53.34%, 均优于对照药剂三氟苯嘧啶(42.85%和51.22%)、噻菌铜(47.76%和23.25%)和叶枯唑(66.97%和17.24%); 化合物8e对柑橘溃疡病菌的抑制率为68.97%, 优于三氟苯嘧啶(49.55%)、噻菌铜(35.85%)和叶枯唑(37.53%), 其中化合物8e对柑橘溃疡病菌的EC₅₀为20.3 μg/mL, 优于噻菌铜(87.9 μg/mL)和叶枯唑(44.5 μg/mL)(表 2).

表 1

表 1 目标化合物8a~8n的生物活性^a

Table 1. Biological activities of the title compounds 8a~8n

下载: 导出CSV

Compd.	杀虫活性(致死率/%, 100 μg/mL)	离体抑菌活性(抑制率/%, 50 μg/mL)
Compd.	白背飞虱	水稻白叶枯病菌	水稻细菌性条斑病菌	柑橘溃疡病菌
8a	40.60±3.54	16.85±3.41	5.51±3.98	31.62±3.25
8b	70.00±6.66	38.12±3.02	30.37±4.68	21.70±0.26
8c	48.67±6.64	51.52±1.36	24.69±6.13	15.11±4.05
8d	70.00±0.01	2.73±3.58	8.12±0.24	49.81±4.40
8e	42.12±4.20	5.72±2.14	3.00±2.42	68.97±1.87
8f	0	6.17±1.24	10.34±3.46	11.91±1.90
8g	34.54±2.91	20.73±2.87	22.69±5.47	14.47±1.51
8h	33.33±0.01	70.91±1.67	53.34±4.03	33.48±4.68
8i	38.70±5.21	16.73±2.89	21.02±2.53	24.01±1.45
8j	40.00±0.01	41.88±3.16	32.04±3.81	20.28±4.54
8k	28.73±1.53	32.06±2.58	26.20±3.72	28.86±3.41
8l	55.17±2.19	23.64±3.03	16.85±4.00	22.00±4.01
8m	23.03±2.01	41.76±1.59	35.71±4.55	18.72±3.21
8n	33.33±0.01	27.94±1.45	23.86±4.00	48.85±0.51
TFM	100.00±0.01	42.85±2.90	51.22±4.69	49.55±2.31
噻菌铜	—	47.76±3.41	23.25±5.60	35.85±3.01
叶枯唑	—	66.97±4.91	17.24±2.01	37.53±2.09
^a“—”代表没有测试.

表 2

表 2 目标化合物8e对柑橘溃疡病菌的EC₅₀值

Table 2. EC₅₀ values of the title compounds 8e against Xcc

下载: 导出CSV

Compd.	Toxic regression equation	r	EC₅₀/(μg•mL^－1)
8e	y＝－0.4761x+5.6499	0.9347	20.3
噻菌铜	y＝1.9447x+1.2190	0.9804	87.9
叶枯唑	y＝1.5561x+2.4354	0.9963	44.5

2. 结论

以三氟苯嘧啶为先导结构, 利用活性亚结构拼接原理, 设计合成了14个结构新颖的1, 3, 4-噻二唑并[3, 2-a]嘧啶酮类介离子化合物.目标化合物的结构通过¹H NMR, ¹³C NMR, ¹⁹F NMR和HRMS进行确认, 并对化合物进行了杀虫活性以及抑菌活性测试.结果表明在浓度为100 μg/mL时, 目标化合物对白背飞虱有一定的杀虫活性.同时在浓度为50 μg/mL时, 部分化合物对水稻白叶枯病菌、水稻细菌性条斑病菌和柑橘溃疡病菌表现出较好的抑制作用.这些研究结果表明1, 3, 4-噻二唑并[3, 2-α]嘧啶类介离子化合物在杀虫剂和抗菌剂的开发与应用中具有一定的潜在价值, 为介离子类化合物的深入研究提供了重要的参考信息.

3. 实验部分

3.1 仪器与试剂

X-4B型数字显示显微熔点测定仪(未校正, 上海), ZF-1型三用紫外分析仪(上海), Bruker ASCEND 400 MHz核磁共振(TMS为内标, DMSO-d₆或CDCl₃为溶剂德国), TSQ 8000型高分辨质谱仪(HRMS, 赛默飞世尔科技有限公司), HP MS 5973型质谱仪(美国惠普公司), TW200酶标仪(瑞士), GR60DA高压灭菌器(中国).所用试剂均为分析纯, 购买于重庆化工集团有限公司; 所有药品购买于上海阿达玛斯试剂有限公司.

3.2 中间体化合物的合成

中间体双(2, 4, 6-三氯苯基)-2-(3-(三氟甲基)苯基)丙二酸酯(4)按照文献[34]的方法合成, 中间体N-((2-氯噻唑-5-基)甲基)-5-(取代硫基)-1, 3, 4-噻二唑-2-胺(7a~7n)按照文献[35]的方法合成.

3.3 目标化合物的合成

参照文献[35]的方法, 称取中间体7a~7n, 1.5 equiv.的中间体4于50 mL圆底烧瓶中, 15 mL甲苯作为反应溶剂, 回流反应6 h, 薄层色谱(TLC) (V_石油醚:V_乙酸乙酯＝1:5)跟踪反应进程.反应结束后, 减压蒸去溶剂, 残渣经柱色谱分离得到新型1, 3, 4-噻二唑并[3, 2-a]嘧啶酮类介离子衍生物8a~8n, 它们均为新化合物.

2-(4-溴苄基)硫基-8-(2-氯噻唑-5-基)甲基-5-氧代-6-[3-(三氟甲基)苯基]-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8a):白色固体, 产率65.5%. m.p. 216.9~217.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.07 (s, 1H, ArH), 8.02 (d, J＝7.8 Hz, 1H, ArH), 7.80 (s, 1H, Thiazole-H), 7.54~7.49 (m, 3H, ArH), 7.49~7.45 (m, 3H, ArH), 5.36 (s, 2H, S-CH₂-Ar), 4.51 (s, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.2, 158.1, 157.5, 154.2, 153.0, 142.9, 136.4, 136.0, 134.2, 133.1, 132.2, 131.9, 128.5, 128.2, 127.9, 126.6 (q, J＝3.8 Hz), 125.1 (q, J＝270.5 Hz), 122.1 (q, J＝3.6 Hz), 122.0, 121.6, 91.8, 46.0, 36.9; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9; MS (EI, 70 eV) m/z (%): 646 ([M+2]⁺), 169 (100), 132 (46), 90 (30); HRMS (ESI) calcd for C₂₃H₁₃O₂N₄BrClF₃S₃[M+H]⁺: 644.90974, found 644.90839.

2-(4-氯苄基)硫基-8-(2-氯噻唑-5-基)甲基-5-氧代-6-[3-(三氟甲基)苯基]-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8b):白色固体, 产率35.0%. m.p. 217.8~218.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.07 (s, 1H, ArH), 8.02 (d, J＝7.9 Hz, 1H, ArH), 7.80 (s, 1H, Thiazole-H), 7.56~7.50 (m, 3H, ArH), 7.47 (d, J＝7.8 Hz, 1H, ArH), 7.40~7.35 (m, 2H), 5.36 (s, 2H, S-CH₂-Ar), 4.53 (s, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆)δ: 161.2, 158.1, 157.5, 154.2, 153.0, 142.9, 136.4, 135.5, 134.2, 133.1, 133.0, 131.9, 129.0, 128.6, 128.5, 128.3, 127.9, 126.6 (q, J＝4.0 Hz), 125.1 (q, J＝272.4 Hz), 122.1 (t, J＝3.6 Hz), 91.8, 46.0, 36.9; ¹⁹F NMR (376 MHz, DMSO-d₆)δ: －60.9; MS (EI, 70 eV) m/z (%): 600 (M⁺), 160 (17), 125 (100), 89 (22), 63 (14); HRMS (ESI) calcd for C₂₃H₁₄O₂N₄Cl₂F₃S₃[M+H]⁺: 600.96025, found 600.95923.

2-戊基硫基-8-(2-氯噻唑-5-基)甲基-5-氧代-6- [3-(三氟甲基)苯基]-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8c):黄色固体, 产率29.7%. m.p. 140.8~141.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.06 (s, 1H, ArH), 8.01 (d, J＝7.9 Hz, 1H, ArH), 7.85 (s, 1H, Thiazole- H), 7.52 (t, J＝7.8 Hz, 1H, ArH), 7.46 (d, J＝7.8 Hz, 1H, ArH), 5.37 (s, 2H, CH₂), 3.28 (t, J＝7.3 Hz, 2H, CH₂CH₂- CH₂CH₂CH₃), 1.77~1.69 (m, 2H, CH₂CH₂CH₂CH₂CH₃), 1.40~1.32 (m, 2H, CH₂CH₂CH₂CH₂CH₃), 1.32~1.25 (m, 2H, CH₂CH₂CH₂CH₂CH₃), 0.85 (t, J＝7.2 Hz, 3H, CH₂- CH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.1, 158.3, 158.1, 154.3, 153.0, 142.9, 136.4, 134.2, 133.2, 128.5, 126.6 (q, J＝4.2 Hz), 125.1 (q, J＝272.1 Hz), 122.1 (q, J＝3.6 Hz), 121.0, 91.8, 46.2, 34.3, 30.6, 28.4, 22.0, 14.3; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9; MS (EI, 70 eV) m/z (%): 546 (M⁺), 157 (30), 132 (100), 43 (46), 71 (15); HRMS (ESI) calcd for C₂₁H₁₉O₂N₄ClF₃S₃[M+H]⁺: 547.03053, found 547.03021.

2-((2-氯噻唑-5-基)甲基)硫基-8-(2-氯噻唑-5-基)甲基-5-氧代-6-[3-(三氟甲基)苯基]-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8d):黄色固体, 产率26.6%. m.p. 90.0~91.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08 (s, 1H, ArH), 8.04 (d, J＝7.9 Hz, 1H, ArH), 7.80 (s, 1H, Thiazole-H), 7.73 (s, 1H, Thiazole-H), 7.55~7.51 (m, 1H, ArH), 7.47 (dd, J＝7.8, 0.6 Hz, 1H, ArH), 5.38 (s, 2H, 2H, S-CH₂-Ar), 4.75 (s, 2H-CH₂); ¹³C NMR (100 MHz, DMSO-d₆)δ: 161.4, 158.1, 157.4, 154.3, 153.0, 151.0, 142.8, 142.6, 137.1, 136.4, 134.2, 133.2, 128.6, 128.2, 126.6 (q, J＝4.0 Hz), 125.6 (q, J＝272.2 Hz), 122.1 (q, J＝3.6 Hz), 91.8, 45.9, 29.7; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9; MS (EI, 70 eV) m/z (%): 607 (M⁺), 167 (13), 132 (100), 71 (24), 45 (18); HRMS (ESI) calcd for C₂₀H₁₁O₂N₅Cl₂F₃S₄[M+H]⁺: 607.91192, found 607.91052.

2-((3-(三氟甲基)苄基)硫基-8-(2-氯噻唑-5-基)甲基-5-氧代-6-[3-(三氟甲基)苯基]-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8e):黄色固体, 产率11.8%. m.p. 70.0~71.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.12 (s, 1H, ArH), 8.06 (d, J＝7.6 Hz, 1H, ArH), 7.96 (s, 1H, Thiazole-H), 7.88 (d, J＝7.7 Hz, 1H, ArH), 7.83 (s, 1H, ArH), 7.66 (d, J＝7.7 Hz, 1H, ArH), 7.57 (d, J＝8.1 Hz, 2H, ArH), 7.50 (d, J＝7.6 Hz, 1H, ArH), 5.39 (s, 2H, Thiazole-CH₂), 4.66 (s, 2H, ArCH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.2, 158.0, 157.5, 154.2, 153.0, 142.8, 138.2, 136.5, 134.2, 134.2, 133.2, 130.0, 129.8, 128.5, 126.7 (q, J＝3.9 Hz), 126.6 (q, J＝3.9 Hz), 125.9, 125.0 (q, J＝3.4 Hz), 124.8 (dd, J＝272.2, 55.4 Hz), 123.7, 122.1 (q, J＝3.7 Hz), 91.7, 46.0, 36.9; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9, －61.1; MS (EI, 70 eV) m/z (%): 634 (M⁺), 159 (100), 132 (75), 109 (25), 86 (25); HRMS (ESI) calcd for C₂₄H₁₄O₂N₄ClF₆S₃[M+H]⁺: 634.98661, found 634.98541.

2-((3, 3, 3-三氟丙基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8f):黄色固体, 产率44.2%. m.p. 180.0~181.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11 (s, 1H, ArH), 8.06 (d, J＝7.8 Hz, 1H, ArH), 7.87 (s, 1H, Thiazole-H), 7.60 (dd, J＝21.3, 18.3 Hz, 1H, ArH), 7.57~7.47 (m, 2H, ArH), 5.44 (s, 2H, Thiazole-CH₂), 3.54~3.48 (m, 2H, S-CH₂), 2.89~2.81 (m, 2H, SCH₂CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.4, 158.0, 157.5, 154.2, 153.1, 142.9, 136.4, 134.2, 133.2, 129.8, 128.5, 126.6 (q, J＝3.7 Hz), 125.1 (q, J＝272.1 Hz), 122.1 (q, J＝3.8 Hz), 91.8, 52.3, 46.0, 32.6 (q, J＝28.2 Hz), 26.4; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －61.0, －64.4; MS (EI, 70 eV) m/z (%): 572 (M⁺), 157 (45), 132 (100), 77 (45), 45 (35); HRMS (ESI) calcd for C₁₉H₁₂O₂N₄ClF₆S₃[M+H]⁺: 572.97096, found 572.96948.

2-((3-氰基丙基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8g):黄色固体, 产率43.3%. m.p. 75.0~76.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H, ArH), 7.95 (dd, J＝4.2, 3.1 Hz, 1H, ArH), 7.60 (s, 1H, Thiazole- H), 7.48 (dd, J＝3.7, 1.4 Hz, 2H, ArH), 5.20 (s, 2H, Thiazole-CH₂), 3.46 (t, J＝7.0 Hz, 2H, S-CH₂), 2.53 (t, J＝6.9 Hz, 2H, S-CH₂CH₂), 2.18 (d, J＝7.0 Hz, 2H, S-CH₂CH₂CH₂-CN); ¹³C NMR (100 MHz, DMSO-d₆) δ: 157.9, 157.3, 156.6, 155.7, 153.8, 142.4, 134.2, 133.7, 130.9, 129.9 (q, J＝31.9 Hz), 128.2, 127.1 (q, J＝3.7 Hz), 124.5 (q, J＝272.5 Hz), 123.1 (dd, J＝7.3, 3.5 Hz), 118.4, 93.1, 46.4, 32.8, 24.6, 16.2; ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.1; MS (EI, 70 eV) m/z (%): 543 (M⁺), 227 (16), 186 (16), 157 (25), 132 (100), 41 (50); HRMS calcd for C₂₀H₁₄O₂N₅ClF₃S₃[M+H]⁺: 543.99448, found 543.99365.

2-((2-(三氟甲基)苄基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8h):黄色固体, 产率45.4%. m.p. 77.0~78.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.13 (s, 1H, ArH), 8.08 (d, J＝7.8 Hz, 1H, ArH), 7.86 (d, J＝9.1 Hz, 2H, Thiazole-H), 7.80 (d, J＝7.7 Hz, 1H, ArH), 7.70 (t, J＝7.5 Hz, 1H, ArH), 7.57 (dd, J＝16.5, 8.1 Hz, 2H, ArH), 7.50 (d, J＝7.8 Hz, 1H, ArH), 5.43 (s, 2H, Thiazole-CH₂), 4.73 (s, 2H, Ar-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.4, 158.1, 157.2, 154.3, 153.0, 142.9, 136.4, 134.2, 133.7, 133.6, 133.2, 133.1, 129.5, 128.6, 128.5, 128.2 (d, J＝24.6 Hz), 127.0 (q, J＝5.3 Hz), 126.6 (q, J＝3.9 Hz), 125.1 (q, J＝272.1 Hz), 124.8 (q, J＝274.3 Hz), 121.03 (q, J＝3.9 Hz), 91.8, 46.0, 34.7; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －58.0, －61.0; MS (EI, 70 eV) m/z (%): 634 (M⁺), 213 (17), 159 (100), 132 (48), 109 (21); HRMS (ESI) calcd for C₂₄H₁₃O₂N₄ClF₆S₃[M+H]⁺: 634.98661, found 634.98560.

2-((4-(三氟甲基)苄基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8i):黄色固体, 产率57.8%. m.p. 85.7~86.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11 (s, 1H, ArH), 8.06 (d, J＝7.8 Hz, 1H, ArH), 7.84 (s, 1H, Thiazole-H), 7.79 (d, J＝8.1 Hz, 2H, ArH), 7.71 (d, J＝8.3 Hz, 2H, ArH), 7.53 (dd, J＝19.2, 7.8 Hz, 2H, ArH), 5.40 (s, 2H, Thiazole-CH₂), 4.66 (s, 2H, Ar-CH₂); ¹³C NMR (100 MHz, CDCl₃)δ: 157.9, 157.3, 156.6, 155.7, 153.8, 142.4, 134.2, 133.7, 130.9, 129.9 (q, J＝31.9 Hz), 128.2, 127.1 (q, J＝3.7 Hz), 124.5 (q, J＝272.5 Hz), 123.1 (dd, J＝7.3, 3.5 Hz), 118.4, 93.1, 46.4, 32.8, 24.6, 16.2; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9, －61.0; MS (EI, 70 eV) m/z (%): 634 (M⁺), 422 (27), 159 (88), 132 (100), 109 (30); HRMS (ESI) calcd for C₂₄H₁₃O₂N₄ClF₆S₃[M+H]⁺: 634.98661, found 634.98535.

2-((3, 5-双(三氟甲基)苄基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8j):黄色固体, 产率46.2%. m.p. 230.6~230.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.35 (s, 2H, ArH), 8.15 (s, 1H, ArH), 8.08 (d, J＝7.8 Hz, 1H, ArH), 8.02 (s, 1H, ArH), 7.82 (s, 1H, Thiazole-H), 7.53 (dd, J＝23.0, 7.8 Hz, 2H, ArH), 5.39 (s, 2H, Thiazole- CH₂), 4.71 (s, 2H, Ar-CH₂); ¹³C NMR (100 MHz, DMSO- d₆)δ: 161.3, 158.1, 157.4, 154.1, 153.0, 142.8, 140.6, 136.5, 134.1, 133.2, 133.2, 131.3, 131.3 (q, J＝32.6 Hz), 130.6 (q, J＝32.9 Hz), 121.9 (dt, J＝7.8, 3.7 Hz), 123.7 (q, J＝273.0 Hz), 125.1 (q, J＝272.1 Hz), 126.6 (q, J＝4.1 Hz), 91.6, 45.9, 36.2;¹⁹F NMR (376 MHz, DMSO-d₆) δ: －61.1, －61.3; MS (EI, 70 eV) m/z (%): 702 (M⁺), 227 (94), 157 (44), 132 (100), 43 (44); HRMS (ESI) calcd for C₂₅H₁₃O₂N₄ClF₉S₃[M+H]⁺: 702.97400, found 702.97314.

2-((3-甲氧基苄基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8k):黄色固体, 产率25.3%. m.p. 81.4~82.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11 (s, 1H, ArH), 8.06 (d, J＝7.8 Hz, 1H, ArH), 7.85 (d, J＝6.7 Hz, 1H, Thiazole-H), 7.58~7.49 (m, 2H, ArH), 7.37~7.30 (m, 2H, ArH), 7.25 (t, J＝7.5 Hz, 1H, ArH), 7.13 (d, J＝7.5 Hz, 1H, ArH), 5.40 (s, 2H, Thiazole-CH₂), 4.54 (s, 2H, Ar-CH₂), 2.30 (s, 3H, OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.1, 158.1, 157.7, 154.3, 153.0, 142.9, 138.3, 136.5, 135.9, 134.2, 133.1, 130.6, 129.1, 129.0, 128.5, 128.2, 127.1, 126.6 (q, J＝3.6 Hz), 125.1 (q, J＝270.6 Hz), 122.1 (q, J＝4.3 Hz), 91.8, 46.0, 37.9, 21.4; ¹⁹F NMR (376 MHz, DMSO-d₆)δ: －60.9; MS (EI, 70 eV) m/z (%): 157 (13), 132 (36), 105 (100), 77 (11); HRMS (ESI) calcd for C₂₄H₁₇O₃N₄ClF₃S₃[M+H]⁺: 597.00979, found 597.00824.

2-((4-甲氧基苄基)硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6-(3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8l):黄色固体, 产率31.9%. m.p. 80.0~81.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.13 (s, 1H, ArH), 8.07 (d, J＝7.6 Hz, 1H, ArH), 7.86 (s, 1H, Thiazole-H), 7.59~7.47 (m, 3H, ArH), 7.34 (t, J＝7.4 Hz, 1H, ArH), 7.06 (d, J＝8.2 Hz, 1H, ArH), 6.93 (t, J＝7.3 Hz, 1H, ArH), 5.41 (s, 2H, Thiazole-CH₂), 4.52 (s, 2H, ArCH₂), 3.85 (s, 3H, OCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.2, 158.0, 158.1, 157.7, 154.3, 153.0, 142.9, 136.4, 134.2, 133.2, 131.5, 130.4, 128.5, 128.2, 126.6 (q, J＝3.7 Hz), 125.1 (q, J＝272.2 Hz), 123.2, 122.1 (q, J＝3.7 Hz), 120.9, 111.6, 91.8, 56.1, 46.1, 33.5; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9; MS (EI, 70 eV) m/z (%): 596 (M⁺), 156 (21), 121 (100), 91 (96), 77 (16); HRMS (ESI) calcd for C₂₄H₁₇O₃N₄ClF₃S₃[M+H]⁺: 597.00979, found 597.00861.

2-(苄基硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6- (3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8m):黄色固体, 产率42.7%. m.p. 75.9~76.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.11 (s, 1H, ArH), 8.06 (d, J＝7.8 Hz, 1H, ArH), 7.84 (s, 1H, Thiazole-H), 7.57~7.50 (m, 4H, ArH), 7.38~7.31 (m, 3H, ArH), 5.40 (s, 2H, Thiazole-CH₂), 4.59 (s, 2H, Ar-CH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.2, 158.1, 157.7, 154.3, 153.0, 142.9, 136.4, 136.2, 134.2, 133.1, 130.0, 129.1, 128.5, 128.4, 128.2, 126.6 (q, J＝3.9 Hz), 125.0 (q, J＝270.5 Hz), 121.1 (q, J＝3.5 Hz), 91.8, 46.0, 37.7; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.9; MS (EI, 70 eV) m/z (%): 566 (M⁺), 157 (8), 132 (18), 91 (100), 65 (12); HRMS (ESI) calcd for C₂₃H₁₄O₂N₄ClF₃NaS₃[M+Na]⁺: 588.98117, found 588.98053.

2-(异丙硫基)-8-((2-氯噻唑-5-基)甲基)-5-氧代-6- (3-(三氟甲基)苯基)-5H-[1, 3, 4]噻二唑并[3, 2-a]嘧啶-8-鎓-7-盐(8n):黄色固体, 产率28.1%. m.p. 78.7~80.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.10 (s, 1H, ArH), 8.05 (d, J＝7.8 Hz, 1H, ArH), 7.88 (d, J＝6.9 Hz, 1H, Thiazole-H), 7.58~7.47 (m, 2H, ArH), 5.41 (s, 2H, Thiazole-CH₂), 3.25 (d, J＝6.8 Hz, 2H, SCH₂), 2.10~1.98 (m, 1H, CH₃CHCH₃), 1.04 (d, J＝6.7 Hz, 6H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆)δ: 161.1, 158.4, 158.1, 154.3, 153.0, 142.9, 136.4, 134.2, 133.2, 128.5, 128.2, 127.4 (q, J＝30.9 Hz), 125.5 (d, J＝4.0 Hz), 124.0 (q, J＝272.1 Hz), 121.01 (q, J＝3.8 Hz), 91.8, 46.2, 42.4, 28.2, 21.9; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －61.0; MS (EI, 70 eV) m/z (%): 532 (M⁺), 186 (34), 132 (78), 72 (85), 57 (100), 43 (98); HRMS (ESI) calcd for C₂₀H₁₇O₂N₄ClF₃S₃[M+H]⁺: 533.01488, found 533.01453.

3.4 目标化合物的生物活性测试

3.4.1 白背飞虱杀虫活性测试

采用喷雾法测试目标化合物在浓度为100 μg/mL时对白背飞虱的致死率.用石英沙将10根水稻幼苗固定于培养皿中, 吸取10头成虫并用二氧化碳进行麻痹, 进行药剂喷施1 mL, 同时以含DMSO的吐温水为空白对照; 喷雾后用除去顶部并用纱布罩住的透明塑料杯罩罩住, 置于23~28 ℃光照恒温箱中培养, 72 h后观察死亡情况; 以毛笔触动, 凡是试虫行动迟缓、取食性明显较少的均判定为虫体死亡.

3.4.2 抑菌活性测试

通过浑浊度法^[36]进行目标化合物对水稻白叶枯病菌、柑橘溃疡病菌和水稻细菌性条斑病菌的离体抑菌活性测试.将化合物8a~8n和95%叶枯唑原药, 20%噻菌铜悬浮剂溶解在120 μL DMSO中, 并用含有吐温-20 (0.1%)的水定容至4 mL, 将1 mL药液加入到含4 mL NB培养基(NB, 3 g牛肉提取物, 1 g酵母粉, 10 g葡萄糖, 5 g蛋白胨和1 L dd H₂O, pH 7.0~7.2)的15 mL试管中, 取200 μL样品用于背景OD₅₉₅值的测定.以无药的相同处理作为阴性对照, 叶枯唑和噻菌铜作为阳性对照.然后加入处于对数生长期的细菌菌液(菌液与药液体积为1:100).将接种的试管在28 ℃, 180 r/min的摇床中连续振荡培养24~48 h.使用酶标仪测量细菌悬浮液在595 nm波长下的OD值.由以下公式计算抑制率I:

抑制率I (%)＝(C－T)/C×100

其中C代表阴性对照组细菌生长的校正浊度值(OD₅₉₅), T代表处理组细菌生长的校正浊度值(OD₅₉₅).

以初筛活性为基础, 使用二倍稀释法, 绘制毒力曲线以获得EC₅₀值.每组设置3个平行实验, 并进行3次重复实验.

辅助材料(Supporting Information) 目标化合物8a~8n的核磁共振氢谱、碳谱、氟谱以及质谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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图 1 目标化合物的设计思路

Figure 1 Design strategy of target compounds

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图式 1 目标化合物8a~8n的合成路线

Scheme 1 Synthetic routes of target compounds 8a~8n

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表 1 目标化合物8a~8n的生物活性^a

Table 1. Biological activities of the title compounds 8a~8n

Compd.	杀虫活性(致死率/%, 100 μg/mL)	离体抑菌活性(抑制率/%, 50 μg/mL)
Compd.	白背飞虱	水稻白叶枯病菌	水稻细菌性条斑病菌	柑橘溃疡病菌
8a	40.60±3.54	16.85±3.41	5.51±3.98	31.62±3.25
8b	70.00±6.66	38.12±3.02	30.37±4.68	21.70±0.26
8c	48.67±6.64	51.52±1.36	24.69±6.13	15.11±4.05
8d	70.00±0.01	2.73±3.58	8.12±0.24	49.81±4.40
8e	42.12±4.20	5.72±2.14	3.00±2.42	68.97±1.87
8f	0	6.17±1.24	10.34±3.46	11.91±1.90
8g	34.54±2.91	20.73±2.87	22.69±5.47	14.47±1.51
8h	33.33±0.01	70.91±1.67	53.34±4.03	33.48±4.68
8i	38.70±5.21	16.73±2.89	21.02±2.53	24.01±1.45
8j	40.00±0.01	41.88±3.16	32.04±3.81	20.28±4.54
8k	28.73±1.53	32.06±2.58	26.20±3.72	28.86±3.41
8l	55.17±2.19	23.64±3.03	16.85±4.00	22.00±4.01
8m	23.03±2.01	41.76±1.59	35.71±4.55	18.72±3.21
8n	33.33±0.01	27.94±1.45	23.86±4.00	48.85±0.51
TFM	100.00±0.01	42.85±2.90	51.22±4.69	49.55±2.31
噻菌铜	—	47.76±3.41	23.25±5.60	35.85±3.01
叶枯唑	—	66.97±4.91	17.24±2.01	37.53±2.09
^a“—”代表没有测试.

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表 2 目标化合物8e对柑橘溃疡病菌的EC₅₀值

Table 2. EC₅₀ values of the title compounds 8e against Xcc

Compd.	Toxic regression equation	r	EC₅₀/(μg•mL^－1)
8e	y＝－0.4761x+5.6499	0.9347	20.3
噻菌铜	y＝1.9447x+1.2190	0.9804	87.9
叶枯唑	y＝1.5561x+2.4354	0.9963	44.5

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