脱氢枞酸酰胺基-3, 4-二氢嘧啶酮衍生物的合成与抗病毒活性研究

doi:10.3969/j.issn.0253-2417.2019.02.007

林产化学与工业 ›› 2019, Vol. 39 ›› Issue (2): 46-52.doi: 10.3969/j.issn.0253-2417.2019.02.007

脱氢枞酸酰胺基-3, 4-二氢嘧啶酮衍生物的合成与抗病毒活性研究

罗云龙^1,²,沈明贵^2,*(),蔡照胜¹,商士斌²,宋湛谦²

1. 中国林业科学研究院林产化学工业研究所；生物质化学利用国家工程实验室；国家林业局林产化学工程重点开放性实验室；江苏省生物质能源与材料重点实验室，江苏南京 210042
2. 盐城工学院化学化工学院，江苏盐城 224051

收稿日期:2018-12-30 出版日期:2019-04-25 发布日期:2019-05-08
通讯作者: 沈明贵 E-mail:shenminggui@sina.com
作者简介:罗云龙(1995—)，男，江西萍乡人，硕士生，主要从事松脂化学利用研究
基金资助:
国家自然科学基金青年基金项目(31500487);中国林业科学研究院中央级公益性科研院所基本科研业务费专项资金(CAFYBB2016QB014)

Synthesis and Antiviral Activity Evaluation of Dehydroabietic Acid Amide Derived 3, 4-Dihydropyrimidinthiones

Yunlong LUO^1,²,Minggui SHEN^2,*(),Zhaosheng CAI¹,Shibin SHANG²,Zhanqian SONG²

1. Institute of Chemical Industry of Forest Products, CAF; National Engineering Lab. for Biomass Chemical Utilization; Key and Open Lab. of Forest Chemical Engineering, SFA; Key Lab. of Biomass Energy and Material, Jiangsu Province, Nanjing 210042, China
2. School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng 224051, China

Received:2018-12-30 Online:2019-04-25 Published:2019-05-08
Contact: Minggui SHEN E-mail:shenminggui@sina.com
Supported by:
国家自然科学基金青年基金项目(31500487);中国林业科学研究院中央级公益性科研院所基本科研业务费专项资金(CAFYBB2016QB014)

摘要/Abstract

摘要：

脱氢枞酸与二氯亚砜反应得到脱氢枞酸酰氯，再与氨基硫脲反应制备脱氢枞基氨基硫脲，脱氢枞基氨基硫脲再与芳香醛和乙酰乙酸乙酯反应，合成了10个脱氢枞酸酰胺基-3, 4-二氢嘧啶酮衍生物，分别为：4-苯基-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3a)、4-(4-甲氧基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3b)、4-(2-甲氧基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3c)、4-(4-甲基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3d)、4-(4-溴苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3e)、4-(4-对三氟甲基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3f)、4-(4-氯苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3g)、4-(2, 6-二氯苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3h)、4-(2-硝基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3i)、4-(3-硝基苯基)-6-甲基-1-脱氢枞酸酰胺基-3, 4-二氢嘧啶-2-硫酮(3j)。通过FT-IR、MS、¹H NMR和¹³C NMR表征了目标化合物结构。选取猴胚胎肾细胞MA-104作为受试细胞，测试了化合物3a~3j的细胞毒性；利用四甲基偶氮唑蓝(MTT)比色法测试了这些化合物对单纯疱疹病毒Ⅰ型(HSV-1)的体外抗病毒活性。数据显示，该系列衍生物的细胞毒性较小，与阳性对照药物利巴韦林相比，化合物3a、3b、3d、3e、3h、3i和3j体现出更小的细胞毒性；化合物3j具有较好的抑制HSV-1活性，半数抑制浓度(IC₅₀)0.465 g/L，选择指数(SI)12.18，达到与阳性对照药物利巴韦林相近的抑制活性(IC₅₀为0.156 g/L，SI为12.6)，其余样品具有较弱的抑制HSV-1活性。

关键词: 松香, 脱氢枞酸, 3, 4-二氢嘧啶酮, 抗病毒

Abstract:

Dehydroabietic acid chloride was prepared via the reaction of dehydroabietic acid and thionylchloride, dehydroabietic acid acylthiosemicarbazide was synthesized by thiosemicarbazone and dehydroabietic acid chloride, followed by the reaction of dehydroabietic acid acylthiosemicarbazide, aromatic aldehydes with ethyl acetate to obtain ten dehydroabietic acid amide derived 3, 4-dihydropyrimidinones: 4-phenyl-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3a), 4-(4-methoxyphenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-di-hydropyrimidine-2-thione (3b), 4-(2-methoxyphenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimi-dine-2-thione (3c), 4-(4-methylphenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3d), 4-(4-bromophenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3e), 4-(4-p-tri-fluoromethylphenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3f). 4-(4-chlorophen-yl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3g), 4-(2, 6-dichlorophenyl)- 6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3h), 4-(2-nitrophenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-dihydropyrimidine-2-thione (3i), 4-(3-nitrophenyl)-6-methyl-1-dehydroabietic acid amide-3, 4-di-hydropyrimidine-2-thione (3j).The target compounds were characterized by FT-IR, MS, ¹H NMR and ¹³C NMR. The cytotoxicity of these 3, 4-dihydropyrimidinone derivatives (compounds 3a-3j) were tested with monkey embryonic kidney cells (MA-104 cells). The antiviral activities against the Herpes simplex virus type Ⅰ (HSV-1) of these derivatives were further evaluated with methyl thiazolyl tetrazolium(MTT) method. The results indicated that the cytotoxicity of these derivatives kept in a low level, compounds 3a, 3b, 3d, 3e, 3h, 3i and 3j showed lower cytotoxicity than the drug ribavirin; compound 3j performed better inhibitory activity of HSV-1(50% inhibitory concentration(IC₅₀) 0.465 g/L, selective index(SI)12.18) which was similar to ribavirin (IC₅₀=0.156 g/L, SI=12.6), and the other compounds showed weak inhibitory activity of HSV-1.

Key words: rosin, dehydroabietic acid, 3, 4-dihydropyrimidinone, antiviral activity

中图分类号:

TQ35
O621.3

罗云龙,沈明贵,蔡照胜,商士斌,宋湛谦. 脱氢枞酸酰胺基-3, 4-二氢嘧啶酮衍生物的合成与抗病毒活性研究[J]. 林产化学与工业, 2019, 39(2): 46-52.

Yunlong LUO,Minggui SHEN,Zhaosheng CAI,Shibin SHANG,Zhanqian SONG. Synthesis and Antiviral Activity Evaluation of Dehydroabietic Acid Amide Derived 3, 4-Dihydropyrimidinthiones[J]. Chemistry and Industry of Forest Products, 2019, 39(2): 46-52.

图/表 3

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参考文献 10

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编号 No.	溶剂 solvent	催化剂用量/% catalyst dosage	分离产率/% yield
1	H₂O	10	35
2	乙腈 acetonitrile	10	51
3	四氢呋喃 tetrahydrofuran	10	41
4	1, 4-二氧六环 1, 4-dioxane	10	40
5	甲苯 toluene	10	27
6	甲醇 methanol	10	78
7	乙醇 ethanol	0	—
8	乙醇 ethanol	5	75
9	乙醇 ethanol	10	82

化合物 compound	半数毒性质量浓度(TC₅₀)/(g·L^-1) 50% toxic concentration	半数抑制浓度(IC₅₀)/(g·L^-1) 50% inhibitory concentration	选择指数(SI) selective index
3a	5.193	2.099	2.474
3b	3.201	1.286	2.489
3c	0.368	0.392	0.939
3d	3.365	2.153	1.563
3e	2.922	0.676	4.322
3f	1.207	0.378	3.193
3g	1.148	0.362	3.171
3h	2.421	1.101	2.198
3i	2.192	1.018	2.1530
3j	5.664	0.465	12.180
利巴韦林 Ribavirin	1.967	0.156	12.600

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脱氢枞酸酰胺基-3, 4-二氢嘧啶酮衍生物的合成与抗病毒活性研究

Synthesis and Antiviral Activity Evaluation of Dehydroabietic Acid Amide Derived 3, 4-Dihydropyrimidinthiones

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