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

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英文篇名：Synthesis and Antiviral Activity Evaluation of Dehydroabietic Acid Amide Derived 3,4-Dihydropyrimidinthiones 作者：罗云龙 ; 沈明贵 ; 蔡照胜 ; 商士斌 ; 宋湛谦 英文作者：LUO Yunlong;SHEN Minggui;CAI Zhaosheng;SHANG Shibin;SONG Zhanqian;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;School of Chemistry and Chemical Engineering,Yancheng Institute of Technology; 关键词：松香 ; 脱氢枞酸 ; 3 ; 4-二氢嘧啶酮 ; 抗病毒 英文关键词：rosin;;dehydroabietic acid;;3,4-dihydropyrimidinone;;antiviral activity 中文刊名：LCHX 英文刊名：Chemistry and Industry of Forest Products 机构：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;盐城工学院 化学化工学院; 出版日期：2019-04-28 出版单位：林产化学与工业 年：2019 期：v.39;No.178 基金：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) 语种：中文; 页：LCHX201902008 页数：7 CN：02 ISSN：32-1149/S 分类号：50-56

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~(13)C 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(IC_(50))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(IC_(50)为0.156 g/L,SI为12.6),其余样品具有较弱的抑制HSV-1活性。
        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(3 a), 4-(4-methoxyphenyl)-6-methyl-1-dehydroabietic acid amide-3,4-di-hydropyrimidine-2-thione(3 b), 4-(2-methoxyphenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimi-dine-2-thione(3 c), 4-(4-methylphenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 d), 4-(4-bromophenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 e), 4-(4-p-tri-fluoromethylphenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 f). 4-(4-chlorophen-yl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 g), 4-(2,6-dichlorophenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 h), 4-(2-nitrophenyl)-6-methyl-1-dehydroabietic acid amide-3,4-dihydropyrimidine-2-thione(3 i), 4-(3-nitrophenyl)-6-methyl-1-dehydroabietic acid amide-3,4-di-hydropyrimidine-2-thione(3 j).The target compounds were characterized by FT-IR, MS, ~1H NMR and ~(13)C NMR. The cytotoxicity of these 3,4-dihydropyrimidinone derivatives(compounds 3 a-3 j) 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 3 a,3 b,3 d,3 e,3 h,3 i and 3 j showed lower cytotoxicity than the drug ribavirin; compound 3 j performed better inhibitory activity of HSV-1(50% inhibitory concentration(IC_(50)) 0.465 g/L,selective index(SI)12.18) which was similar to ribavirin(IC_(50)=0.156 g/L,SI=12.6),and the other compounds showed weak inhibitory activity of HSV-1.

引文

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