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张成路, 程安琪, 唐杰, 国阳, 孙丽杰, 袭焕. 新型5-脂肪基-1,2,4-三唑曼尼希碱的合成及生物活性[J]. 应用化学, 33(5): 554-564
ZHANG Chenglu, CHENG Anqi, TANG Jie, et al. Synthesis and Biological Activity of the Novel Mannich Bases of 5-Alkyl-1,2,4-triazole[J]. Chinese Journal of Applied Chemistry, 33(5): 554-564  
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新型5-脂肪基-1,2,4-三唑曼尼希碱的合成及生物活性
张成路*, 程安琪, 唐杰, 国阳, 孙丽杰, 袭焕
辽宁师范大学化学化工学院 辽宁 大连116029
通讯联系人:张成路,教授; Tel:0411-82158329; E-mail:zhangchenglu@lnnu.edu.cn; 研究方向:药物合成
收稿日期:2015-07-28 修回日期:2015-11-02 接受日期:2015-12-07
基金:辽宁省教育厅科学技术项目资助(2009A426);
摘要

设计并合成了22个具有长脂肪链取代的新型三唑曼尼希碱,研究了其植物生长调节活性、除草活性和对细胞周期分裂蛋白25B(CDC25B)抑制活性,结果发现,多数目标分子表现出优良的促进细胞生长素活性和除草活性,表明该类分子有望成为优良的新型农药;对CDC25B抑制活性筛选发现一种曼尼希碱具有优良的CDC25B抑制活性,其IC50值低于阳性参照物正钒酸钠,有望成为肿瘤治疗的药物先导物。

关键词: 脂肪基-三唑; 曼尼希碱; 植物生长调节; 除草; 细胞周期分裂蛋白25B抑制剂
中图分类号:O626 文献标志码:A 文章编号:1000-0518(2016)05-0554-11
Synthesis and Biological Activity of the Novel Mannich Bases of 5-Alkyl-1,2,4-triazole
ZHANG Chenglu, CHENG Anqi, TANG Jie, GUO Yang, XI Huan
College of Chemistry and Chemical Engineering,Liaoning Normal University,Dalian,Liaoning 116029,China
Corresponding author:ZHANG Chenglu, professor; Tel:0411-82158329; E-mail:zhangchenglu@lnnu.edu.cn; Research interests:drug synthesis
Received:2015-07-28 Revised:2015-11-02 Accepted:2015-12-07
Fund:Supported by Technology Research Program of Liaoning Provincial Department of Education(No.2009A426)
Abstract

Twenty-two novel Mannich bases of 5-alkyl-1,2,4-triazole were designed and synthesized to evaluate their biological activities. The plant growth regulating activity, herbicidal activity and the inhibitory activity on cell division cycle protein 25B(CDC25B) of those molecules were screened. Most of the molecules exhibit good cytokinin activity and herbicidal activity, indicating their potential as novel pesticide. One of these molecules performs good inhibitory activity against CDC25B, and is a potential leading compound for anti-concer drug design.

Keyword: alkyl-triazole; Mannich base; plant growth regulator; herbicidal activity; inhibitors against CDC25B

含有1,2,4-三唑、吗啉和哌嗪等结构基元的分子已成为构成许多传统药物的重要活性组块。 如具有类似植物激素活性、能阻止秧苗顶端生长优势和促进侧芽滋生的植物生长调节剂多效唑(Paclobutrazol,Scheme 1)已广泛应用于调控作物的生长发育,使得利用植物生长调节剂调控作物生长发育进程成为现实[1,2,3,4,5,6];具有防治各种蚜虫的唑蚜威(Triaguron,Scheme 1)、镇咳作用的福尔可定(Pholcodine,Scheme 1)和左羟丙哌嗪(Levodropropizine,Scheme 1)等也已广泛应用于农业生产和临床疾病治疗中。 含氮杂环分子还被广泛用作除草剂,如含有三嗪环的除草剂西玛津等。 因此将多种药效基团构筑于同一分子中,以筛选活性优良的新型药物分子已成为探索新药的重要策略之一。

Scheme 1 Bioactive molecules containing triazole, morpholine and piperazine

采用多组分合成法,目标分子更易通过简捷、高效的途径获得。 多组分Mannich反应作为重要的原子经济型反应,已成为许多合成药物和天然产物合成的重要反应之一[7,8,9,10,11]。 植物生长调剂活性的研究主要可通过药物分子对细胞分裂素活性、生长素活性和除草活性评价,其中稗草分布广、危害大,成为筛选除草剂时的主要研究对象。 CDC25B(细胞周期分裂蛋白25B,cell division cycle 25 homolog B)与肿瘤或癌症的恶性程度有关,如果下调CDC25B的表达,会引起细胞周期的阻滞,从而抑制肿瘤细胞增殖,CDC25B抑制剂的研究已成为恶性肿瘤治疗的新的切入点[12,13,14]。

为筛选新型农药和抗肿瘤药物先导物,本文设计了22个新型5-脂肪基-1,2,4-三唑曼尼希碱分子,评价了目标分子的植物生长调节活性、除草活性和对CDC25B的抑制活性。 目标化合物合成路线如Scheme 2所示。

Scheme 2 Synthesis route of target compounds

1 实验部分
1.1 仪器和试剂

BRUKER Avance-500MHz型核磁共振波谱仪(瑞士Bruker公司),氘代氯仿为溶剂;TENSOR27型傅里叶变换红外光谱仪(德国Bruker AXS公司);5-戊基-1,2,4-三唑(PT)和5-十一烷基-1,2,4-三唑(UT)参考文献[15]方法合成,其余试剂均购自国药集团化学试剂有限公司。

1.2 实验方法

1.2.1 脂肪基三唑希夫碱(PTS和UTS)的合成通法 取0.1 mol 4-氨基-5-脂肪基-4H-1,2,4-三唑3-巯醇(PT和UT)于带球形冷凝管、恒压滴液漏斗和温度计的50 mL三口瓶中,加入10 mL无水乙醇,稍加热使其溶解。 称量(量取)0.12 mol的芳香醛,用2 mL无水乙醇溶解后在室温下滴加,滴加完毕继续加热至回流,加入几滴浓硫酸作为催化剂,TLC监测反应进程,待4-氨基-5-脂肪基-4 H-1,2,4-三唑3-巯醇(PT和UT)全部反应,撤掉热源,加少量水搅拌直至不再有固体析出,静置,抽滤,石油醚/乙酸乙酯(体积比1:1)重结晶,得1,2,4-三唑希夫碱衍生物。

4-(对甲氧基苯基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSa):淡黄色固体,收率88.6%,mp 96.0~97.0 ℃。1H NMR(CDCl3,500 MHz), δ:10.69(s,1H),10.15(s,1H),7.85~7.80(m,2H),7.02~6.98(m,2H),3.89(s,3H),2.80(t, J=7.6 Hz,2H),1.77~1.72(m,2H),1.39~1.34(m,4H),0.91(t, J=7.0 Hz,3H);IR(KBr), σ/cm-1:3443,3118,2920,2853,1655,1607,1465,1397,1255,723。

4-(对甲氧基苯基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSa):橘黄色固体,收率83.5%,mp 128.6~129.7 ℃。1H NMR(CDCl3,500 MHz), δ:11.02(s,1H),10.43(s,1H),7.82(dd, J=1.8 Hz,7.0 Hz,2H),7.00(dd, J=1.8 Hz,7.0 Hz,2H),3.88(s,3H),2.80(t, J=7.6 Hz,2H),1.76~1.71(m,2H),1.40~1.36(m,2H),1.34~1.25(m,14H),0.89(t, J=6.9 Hz,3H);IR(KBr), σ/cm-1:3443,3118,2920,2853,1607,1509,1405,1355,1289,1155,1005,837。

4-(苯烯丙基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSb):淡黄色固体,收率70.6%,mp 96.0~97.0 ℃。1H NMR(CDCl3,500 MHz), δ:11.07(s,1H),10.48(s,1H),7.62~7.60(m,2H),7.45~7.40(m,3H),7.31(d, J=16.0 Hz,1H),7.12(dd, J=9.4 Hz,16.0 Hz,1H),2.80(t, J=7.6 Hz,2H),1.75(m,2H),1.39(m,4H),0.87(t, J=6.6 Hz,3H);IR(KBr), σ/cm-1:3443,3118,2914,2832,1647,1594,1460,1390,1267,710。

4-(苯烯丙基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSb):淡黄色固体,收率78.1%,mp 75.8~77.2 ℃。1H NMR(CDCl3,500 MHz), δ:11.02(s,1H),10.46(s,1H),7.63~7.61(m,2H),7.44~7.40(m,3H),7.32(d, J=16.0 Hz,1H),7.12(dd, J=9.4 Hz,16.0 Hz,1H),2.80(t, J=7.6 Hz,2H),1.77~1.73(m,2H),1.39~1.35(m,2H),1.31~1.26(m,14H),0.92(t, J=7.0 Hz,3H);IR(KBr), σ/cm-1:3443,3118,2920,2853,1655,1607,1465,1397,1255,723。

4-(对氯苯基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSc):白色固体,收率85.2%,mp 102.1~103.3 ℃。1H NMR(CDCl3,500 MHz), δ:11.07(s,1H),10.47(s,1H),7.81(d, J=8.5 Hz,2H),7.48(d, J=8.5 Hz,2H),2.83(t, J=7.6 Hz,2H),1.79~1.74(m,2H),1.42~1.33(m,4H),0.92(t, J=7.0 Hz,3H);IR(KBr), σ/cm-1:3443,3128,2920,2843,1655,1588,1465,1395,1274,721。

4-(对氯苯基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSc):白色固体,收率88.6%,mp 108.4~109.9 ℃。1H NMR(CDCl3,500 MHz), δ:11.06(s,1H),10.62(s,1H),7.82(d, J=8.4 Hz,2H),6.99(d, J=8.4 Hz,2H),2.77(t, J=7.7 Hz,2H),1.75~1.69(m,2H),1.38~1.35(m,2H),1.31~1.25(m,14H),0.89(t, J=6.4 Hz,3H);IR(KBr), σ/cm-1:3445,3110,2917,2857,1605,1407,1397,1285,723。

4-(对氟苯基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSd):白色固体,收率80.2%,mp 113.8~115.0 ℃。1H NMR(CDCl3,500 MHz), δ:10.96(s,1H),10.40(s,1H),7.89~7.86(m,2H),7.19~7.16(m,2H),2.83(t, J=7.60 Hz,2H),1.80~1.74(m,2H),1.41~1.34(m,4H),0.92~0.89(m,3H);IR(KBr), σ/cm-1:3442,3118,2928,2853,1653,1600,1457,1392,1265,720。

4-(对氟苯基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSd):淡黄色固体,收率79.4%,mp 101.3~102.5 ℃。1H NMR(CDCl3,500 MHz), δ:11.05(s,1H),10.60(s,1H),7.89~7.86(m,2H),7.19~7.15(m,2H),2.80~2.78(m,2H),1.78~1.64(m,2H),1.41~1.36(m,2H),1.32~1.25(m,14H),0.89(t, J=6.8 Hz,3H);IR(KBr), σ/cm-1:3436,3114,2921,2850,1607,1465,1383,1287,833。

4-(2-吡啶基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSe):黄绿色固体,收率78.9%,mp 107.5~108.6 ℃。1H NMR(CDCl3,500 MHz), δ:11.06(s,1H),10.62(s,1H),8.78~8.77(m,2H),8.09(d, J=7.70 Hz,1H),7.84~7.81(m,1H),7.43~7.41(m,1H),2.86(t, J=7.6 Hz,2H),1.80~1.76(m,2H),1.41~1.25(m,4H),0.92(t, J=6.6 Hz,3H);IR(KBr), σ/cm-1:3440,3123,2945,2837,1659,1600,1473,1389,1275,714。

4-(2-吡啶基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSe):淡黄色固体,收率74.5%,mp 122.4~123.4 ℃。1H NMR(CDCl3,500 MHz), δ:11.04(s,1H),10.63(s,1H),7.88~7.85(m,2H),7.18(t, J=8.6 Hz,2H),2.79(t, J=7.6 Hz,2H),1.76~1.70(m,2H),1.39~1.35(m,2H),1.32~1.26(m,14H),0.92(t, J=6.9 Hz,3H);IR(KBr), σ/cm-1:3438,3117,2916,2859,1609,1445,1337,1276,815。

4-(呋喃-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSf):棕色固体,收率81.2%,mp 104.1~105.4 ℃。1H NMR(CDCl3,500 MHz), δ:11.07(s,1H),10.58(s,1H),7.67(d, J=1.7 Hz,1H),7.06(t, J=3.4 Hz,1H),6.60(dd, J=1.8 Hz,3.5 Hz,1H),2.82(t, J=7.6 Hz,2H),1.75(m,2H),1.39(m,4H),0.87(t, J=6.6 Hz,3H);IR(KBr), σ/cm-1:3446,3109,2920,2853,1653,1598,1470,1389,1276,709。

4-(呋喃-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSf):淡黄色固体,收率80.3%,mp 75.0~76.4 ℃。1H NMR(CDCl3,500 MHz), δ:11.02(s,1H),10.58(s,1H),7.66(d, J=1.5 Hz,1H),7.04(d, J=3.5 Hz,1H),6.59(dd, J=1.8 Hz,3.5 Hz,1H),2.78(t, J=7.6 Hz,2H),1.75~1.72(m,2H),1.39~1.32(m,14H),0.91~0.89(m,3H);IR(KBr), σ/cm-1:3444,3103,2917,2859,1650,1588,1459,1382,1275,709。

4-(二茂铁基-2-甲烯基氨基)-5-戊基-4 H-1,2,4-三唑-3-硫醇(PTSg):橘黄色固体,收率73.2%,mp 146.3~147.7 ℃。1H NMR(CDCl3,500 MHz), δ:11.04(s,1H),10.46(s,1H),4.76(t, J=1.8 Hz,2H),4.57(t, J=1.8 Hz,2H),4.35(s,5H),2.72(t, J=7.6 Hz,2H),1.73(t, J=7.5 Hz,2H),1.37~1.34(m,4H),0.91~0.89(m,3H);IR(KBr), σ/cm-1:3439,3118,2920,2853,1605,1405,1321,1289,1171,1021,821,503。

4-(二茂铁基-2-甲烯基氨基)-5-十一烷基-4 H-1,2,4-三唑-3-硫醇(UTSg):橘黄色固体,收率80%,mp 128.6~129.7 ℃。1H NMR(CDCl3,500 MHz), δ:11.00(s,1H),10.13(s,1H),4.76(t, J=1.8 Hz,2H),4.57(t, J=1.8 Hz,2H),4.35(s,5H),1.77~1.73(m,2H),1.38~1.33(m,2H),1.34~1.24(m,14H),0.92(t, J=7.0 Hz,3H);IR(KBr), σ/cm-1:3442,3115,2916,2848,1610,1407,1334,1289,1181,1041,832,507。

1.2.2 脂肪基三唑曼尼希碱的合成通法 于50 mL的圆底烧瓶中,加入脂肪基三唑希夫碱(0.5 mmol)和乙醇5 mL。 加热至回流后,加入37%甲醛(0.06 mL,0.6 mmol)。 搅拌10 min后,加入吗啉(0.6 mmol)[ N-甲基哌嗪(0.6 mmol)或哌嗪(0.3 mmol)]。 原料完全反应后,降至室温,加入少量水至固体不再析出。 静置过夜,抽滤。 固体用乙醇重结晶,得目标产品。

2-((4-甲基哌嗪-1-基)甲基)-(4-甲氧苯烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮(PTSPa):白色粉末,mp 68.5~69.5 ℃,收率78.4%。1H NMR(CDCl3,500 MHz), δ:10.11(s,1H),7.83(d, J=8.8 Hz,2H),7.00(d, J=8.8 Hz,2H),5.13(s,2H),3.88(s,3H),2.89(s,4H),2.78(t, J=7.7 Hz,2H),2.46(s,4H),2.28(s,3H),1.78~1.71(m,2H),1.39~1.35(m,4H),0.91(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.64,162.57,161.48,150.83,130.52,125.38,114.38,68.82,55.45,54.63,49.59,45.30,31.20,25.84,25.05,22.12,13.82;IR(KBr), σ/cm-1:2931,2853,2796,1587,1522,1424,1326,825;HRMS(positive-SIMS), m/z: 417.2432(M+1)(计算值C37H57N9S2:417.2431)。

2-((4-甲基哌嗪-1-基)甲基)-(4-甲氧苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮(UTSPa):白色粉末,mp 105.9~107.2 ℃,收率80.3%。1H NMR(CDCl3,500 MHz), δ:10.11(s,1H),7.82(d, J=8.4 Hz,2H),6.99(d, J=8.4 Hz,2H),5.14(s,2H),3.88(s,3H),2.89(s,4H),2.77(t, J=7.7 Hz,2H),2.46(s,4H),2.29(s,3H),1.75~1.69(m,2H),1.38~1.35(m,2H),1.31~1.25(m,14H),0.89(t, J=6.4 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.64,162.57,161.48,150.83,130.52,125.38,114.38,68.82,55.45,54.63,49.59,45.30,31.84,29.52,29.02,26.16,25.07,22.66,14.06;IR(KBr), σ/cm-1:3443,3332,3135,3008,2922,2844,2794,1659,1605,1515,1399,1319,1257,1167,1069,953,863,737,613,523;HRMS(positive-SIMS), m/z:501.3370(M+1)(计算值C37H57N9S2:501.3370)。

2-((4-甲基哌嗪-1-基)甲基)-4-((3-苯烯丙基)氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮(PTSPb):淡黄色粉末,mp 88.6~90.0 ℃,收率53.7%。1H NMR(CDCl3,500 MHz), δ:10.41(s,1H),7.69-7.66(m,2H),7.43~7.41(m,3H),7.37(d, J=16.0 Hz,1H),7.16~7.14(m,1H),5.11(s,2H),2.89(s,4H),2.78(t, J=7.7 Hz,2H),2.46(s,4H),2.28(s,3H),1.77~1.73(m,2H),1.31~1.26(m,4H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.54,161.52,150.85,137.26,135.27,134.14,128.62,128.50,127.98,126.37,68.87,54.66,49.53,45.30,31.28,25.86,25.03,22.13,13.87;IR(KBr), σ/cm-1:3433,2932,2844,1587,1492,1360,835;HRMS(positive-SIMS), m/z:413.2489(M+1)(计算值C37H57N9S2:413.2482)。

2-((4-甲基哌嗪-1-基)甲基)-4-((3-苯烯丙基)氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮(UTSPb):淡黄色粉末,mp 96.4~97.7 ℃,收率64.8%。1H NMR(CDCl3,500 MHz), δ:10.53(s,1H),7.66~7.63(m,2H),7.47~7.43(m,3H),7.33(d, J=16.0 Hz,1H),7.12(dd, J=9.4 Hz,16.0 Hz,1H),5.10(s,2H),2.87(s,4H),2.79(t, J=7.7 Hz,2H),2.46(s,4H),2.28(s,3H),1.75~1.71(m,2H),1.42~1.36(m,2H),1.33~1.25(m,14H),0.88(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.55,161.55,150.85,137.24,135.25,134.16,128.65,128.55,127.94,126.33,68.85,54.66,49.57,45.35,31.82,29.57,29.01,26.16,25.03,22.64,14.02;IR(KBr), σ/cm-1:3433,2932,2844,1587,1492,1360,845;HRMS(positive-SIMS), m/z:497.3426(M+1)(计算值C37H57N9S2:497.3421)。

2-(吗啉代甲基)-(4-甲氧基苯烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮(PTSMa):白色粉末,mp 79.1~80.2 ℃,收率81.0%。1H NMR(CDCl3,500 MHz), δ:10.14(s,1H),7.83(d, J=8.8 Hz,2H),7.00(d, J=8.8 Hz,2H),5.11(s,2H),3.88(s,3H),3.70(t, J=4.6 Hz,4H),2.84(t, J=4.7 Hz,4H),2.80(t, J=7.6 Hz,2H),1.78~1.70(m,2H),1.39~1.25(m,4H),0.91(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:163.07,162.61,161.46,150.85,130.54,125.31,114.40,68.77,55.44,50.46,31.23,25.78,25.00,22.16,13.87;IR(KBr), σ/cm-1:3446,3134,2961,2853,1613,1515,1440,1319,1297,1257,1167,1113,1023,969,853,827,783,729;HRMS(positive-SIMS), m/z:404.2113(M+1)(计算值C37H57N9S2: 404.2115)。

2-(吗啉代甲基)-(4-甲氧基苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮(UTSMa):白色粉末,mp 75.4~77.0 ℃,收率83.1%。1H NMR(CDCl3,500 MHz), δ:10.15(s,1H),7.82(dd, J=1.8 Hz,7.0 Hz,2H),7.00(dd, J=1.8 Hz,7.0 Hz,2H),5.10(s,2H),3.88(s,3H),3.71(t, J=4.6 Hz,4H),2.84(t, J=4.7 Hz,4H),2.80(t, J=7.6 Hz,2H),1.76~1.71(m,2H),1.40~1.36(m,2H),1.34~1.25(m,14H),0.89(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:163.07,162.62,161.46,150.86,130.55,125.32,114.40,68.77,66.90,55.45,50.46,31.89,29.58,29.09,26.15,25.05,22.66,14.08;IR(KBr), σ/cm-1:3443,3134,2921,2853,1665,1598,1507,1404,1326,1309,1255,1167,1113,1069,953,855,783,729,621,513;HRMS(positive-SIMS), m/z:488.3058(M+1)(计算值C37H57N9S2:488.3054)。

2-(吗啉代甲基)-4-(3-苯烯丙基)氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮(PTSMb):淡黄色粉末,mp 78.2~79.0 ℃,收率65.9%。1H NMR(CDCl3,500 MHz), δ:10.44(s,1H),7.65~7.62(m,2H),7.43~7.41(m,3H),7.34(d, J=16.0 Hz,1H),7.14~7.12(m,1H),5.12(s,2H),3.72(t, J=4.8 Hz,4H),2.83(t, J=4.8 Hz,4H),2.78(t, J=7.7 Hz,2H),1.77~1.73(m,2H),1.31~1.26(m,4H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.57,161.50,150.84,137.24,135.29,134.12,128.67,128.51,127.90,126.32,68.88,66.90,50.90,31.23,25.81,25.00,22.16,13.87;IR(KBr), σ/cm-1:3430,2942,2844,1587,1492,1395,875;HRMS(positive-SIMS), m/z:400.2169(M+1)(计算值C37H57N9S2:400.2166)。

2-(吗啉代甲基)-4-(3-苯烯丙基)氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮(UTSMb):淡黄色粉末,mp 68.3~69.7 ℃,收率66.2%。1H NMR(CDCl3,500 MHz), δ:10.41(s,1H),7.68~7.66(m,2H),7.48~7.45(m,3H),7.39(d, J=16.0 Hz,1H),7.14~7.12(m,1H),5.13(s,2H),3.72(t, J=4.8 Hz,4H),2.83(t, J=4.8 Hz,4H),2.78(t, J=7.7 Hz,2H),1.78~1.75(m,2H),1.38~1.35(m,2H),1.33~1.26(m,14H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.53,161.51,150.81,137.26,135.23,134.16,128.62,128.51,127.93,126.36,68.82,66.90,50.92,31.82,29.52,29.08,26.18,25.07,22.68,14.03;IR(KBr), σ/cm-1:3430,2942,2844,1587,1492,1395,875;HRMS(positive-SIMS), m/z:484.3103(M+1)(计算值C37H57N9S2:484.3105)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-甲氧苯烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDa):白色粉末,mp 184.1~185.2 ℃,收率88.6%。1H NMR(CDCl3,500 MHz), δ:10.13(s,2H),7.82(d, J=8.8 Hz,4H),7.00(d, J=8.8 Hz,4H),5.10(s,4H),3.88(s,6H),2.86(s,8H),2.78(t, J=7.6 Hz,4H),1.76~1.72(m,4H),1.38~1.35(m,8H),0.91~0.89(m,6H);13C NMR(CDCl3,125 MHz), δ:163.06,162.61,161.46,150.84,130.53,125.32,114.42,68.77,55.46,50.46,31.24,25.78,25.00,22.10,13.80;IR(KBr), σ/cm-1:3433,2931,2843,1580,1434,1377,815;HRMS(positive-SIMS), m/z:719.3636(M+1)(计算值C37H57N9S2:719.3632)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-甲氧苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDa):白色粉末,mp 172.4~173.5 ℃,收率85.8%。1H NMR(CDCl3,500 MHz), δ:10.14(s,H),7.82(d, J=1.4 Hz,2H),6.99(d, J=8.8 Hz,2H),5.10(s,2H),3.88(s,3H),2.86(s,4H),2.78(t, J=7.6 Hz,2H),1.76~1.70(m,2H),1.40~1.35(m,2H),1.31~1.25(m,14H),0.89(t, J=6.8 Hz,3H);13C NMR(CDCl3,125 MHz), δ:163.07,162.62,161.46,150.86,130.55,125.32,114.40,68.77,55.46,50.46,31.83,29.56,29.07,26.18,25.06,22.66,14.03;IR(KBr), σ/cm-1:3443,3134,2912,2854,1675,1598,1404,863;HRMS(positive-SIMS), m/z:803.4575(M+1)(计算值C37H57N9S2:803.4571)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-氯苯烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDb):白色粉末,mp 204.1~205.2 ℃,收率90.2%。1H NMR(CDCl3,500 MHz), δ:10.51(s,2H),7.80(d, J=8.5 Hz,4H),7.00(d, J=8.5 Hz,4H),5.11(s,4H),2.85(s,8H),2.82~2.76(m,4H),1.76~1.72(m,4H),1.40~1.26(m,8H),0.92~0.89(m,6H);13C NMR(CDCl3,125 MHz), δ:162.56,162.53,161.55,150.87,130.73,129.07,116.34,68.87,50.44,31.28,25.86,25.06,22.13,13.83;IR(KBr), σ/cm-1:3433,2931,2843,1580,1434,1377,815;HRMS(positive-SIMS), m/z:727.2640(M+1)(计算值C37H57N9S2:727.2642)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-氯苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDb):白色粉末,mp 178.4~180.2 ℃,收率73.1%;1H NMR(CDCl3,500 MHz), δ:10.51(s,2H),7.80(d, J=8.5 Hz,4H),7.00(d, J=8.5 Hz,4H),5.11(s,4H),2.85(s,8H),2.82~2.76(m,4H),1.76~1.72(m,4H),1.40~1.26(m,28H),0.92~0.89(m,6H);13C NMR(CDCl3,125 MHz), δ:162.59,162.52,161.55,150.87,130.73,129.00,116.34,68.87,50.46,31.86,29.55,29.06,26.17,25.06,22.68,14.04;IR(KBr), σ/cm-1:3433,3135,2921,2853,1665,1587,1394,862;HRMS(positive-SIMS), m/z:811.3584(M+1)(计算值C37H57N9S2:811.3581)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-氟苯烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDc):白色粉末,mp 186.0~187.2 ℃,收率82.2%。1H NMR(CDCl3,500 MHz), δ:10.42(s,1H),7.88~7.85(m,2H),7.18(t, J=8.6 Hz,2H),5.09(s,2H),2.86(s,4H),2.79(t, J=7.6 Hz,2H),1.78~1.72(m,2H),1.41~1.34(m,4H),0.92(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.54,162.50,161.56,150.83,130.76,129.08,116.39,68.83,50.45,31.21,25.83,25.04,22.15,13.85;IR(KBr), σ/cm-1:3433,2922,2836,1587,1512,1434,1326,831;HRMS(positive-SIMS), m/z:695.3233(M+1)(计算值C37H57N9S2:695.3233)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(4-氟苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDc):白色粉末,mp 170.7~171.5 ℃,收率78.3%。1H NMR(CDCl3,500 MHz), δ:10.42(s,1H),7.88~7.85(m,2H),7.18(t, J=8.6 Hz,2H),5.09(s,2H),2.87(s,4H),2.79(t, J=7.6 Hz,2H),1.76~1.70(m,2H),1.39~1.35(m,2H),1.31~1.25(m,14H),0.89(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.54,162.50,161.56,150.83,130.76,129.08,116.39,68.83,50.45,31.84,29.55,29.07,26.19,25.03,22.65,14.07;IR(KBr), σ/cm-1:3425,3124,2911,2796,1675,1597,1394,835;HRMS(positive-SIMS), m/z:779.4175(M+1)(计算值C37H57N9S2:779.4172)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(吡啶-2-基甲烯基氨基)-5-戊基-1 H-1,2,4-三唑-5(4 H)-硫酮)(PTSDd):淡黄色粉末,mp 188.7~189.7 ℃,收率83.1%.。1H NMR(CDCl3,500 MHz), δ:10.66(s,1H),8.75(dd, J=1.1 Hz,4.5 Hz,1H),8.08(d, J=7.9 Hz,1H),7.83(ddd, J=1.5 Hz,7.7 Hz,15.5 Hz,1H),7.41(dddd, J=1.0 Hz,4.8 Hz,7.4 Hz,17.3 Hz,1H),5.10(s,2H),2.86(s,4H),2.83~2.79(m,2H),1.79~1.73(m,2H),1.42~1.33(m,4H),0.92~0.90(m,3H);13C NMR(CDCl3,125 MHz), δ:162.52,161.51,160.05,150.87,150.15,136.54,125.68,121.65,68.83,50.45,31.22,25.87,25.00,22.15,13.87;IR(KBr), σ/cm-1:3443,3134,2952,2844,2342,1675,1600,1434,1326,845;HRMS(positive-SIMS), m/z:661.3324(M+1)(计算值C37H57N9S2:661.3326)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(吡啶-2-基甲烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDd):淡黄色粉末,mp 188.9~190.2 ℃,收率67.9%。1H NMR(CDCl3,500 MHz), δ:10.67(s,1H),7.75~7.74(m,1H),8.09(d, J=8.0 Hz,1H),7.84~7.80(m,1H),7.41~7.39(m,1H),5.10(s,2H),2.88(s,4H),2.80(t, J=7.6 Hz,2H),1.75-1.70(m,2H),1.38-1.35(m,2H),1.31-1.25(m,14H),0.89(t, J=6.9 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.52,161.51,160.05,150.87,150.15,136.54,125.68,121.65,68.83,50.45,31.82,29.56,29.07,26.15,25.03,22.64,14.05;IR(KBr), σ/cm-1:3433,3124,2952,2844,2342,1675,1607,1484,1346,855;HRMS(positive-SIMS), m/z:745.4269(M+1)(计算值C37H57N9S2:745.4265)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(呋喃-2-基甲烯基氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDe):白色粉末,mp 164.3~165.1 ℃,收率76.0%。1H NMR(CDCl3,500 MHz), δ:10.30(s,1H),7.66(d, J=1.4 Hz,1H),7.04(d, J=3.5 Hz,1H),6.60(dd, J=1.8 Hz,3.5 Hz,1H),5.13(s,2H),2.86(s,4H),2.79(t, J=7.6 Hz,2H),1.76~1.72(m,2H),1.39~1.36(m,4H),0.92~0.89(m,3H);13C NMR(CDCl3,125 MHz), δ:162.57,161.50,150.84,149.67,146.67,118.29,112.48,68.84,50.46,31.26,25.87,25.08,22.15,13.85;IR(KBr), σ/cm-1:3443,3134,2932,2844,1665,1617,1386,855;HRMS(positive-SIMS), m/z:639.3001(M+1)(计算值C37H57N9S2:639.3006)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-(呋喃-2-基甲烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDe):白色粉末,mp 169.8~170.8 ℃,收率78.2%。1H NMR(CDCl3,500 MHz), δ:10.30(s,1H),7.66(d, J=1.4 Hz,1H),7.04(d, J=3.5 Hz,1H),6.60(dd, J=1.8 Hz,3.5 Hz,1H),5.13(s,2H),2.86(s,4H),1.77~1.73(m,2H),1.39~1.35(m,2H),1.31~1.26(m,14H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.57,161.50,150.84,149.67,146.67,118.29,112.48,68.84,50.46,31.86,29.54,29.02,26.13,25.08,22.68,14.09;IR(KBr), σ/cm-1:3443,3135,2921,2843,1675,1587,1386,835;HRMS(positive-SIMS), m/z:723.3941(M+1)(计算值C37H57N9S2:723.3945)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-((3-苯烯丙基)氨基)-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDf) 淡黄色粉末,mp 168.5~169.9 ℃,收率62.2%。1H NMR(CDCl3,500 MHz), δ:10.46(s,1H),7.73~7.70(m,2H),7.47~7.44(m,3H),7.36(d, J=16.0 Hz,1H),7.17~7.15(m,1H),5.11(s,2H),2.89(s,4H),2.78(t, J=7.7 Hz,2H),1.77~1.73(m,2H),1.31~1.2(m,4H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.54,161.53,150.84,137.23,135.23,134.17,128.65 128.55,127.96,126.36,68.86,50.43,31.23,25.87,25.02,22.16,13.88;IR(KBr), σ/cm-1:3433,2922,2844,1587,1512,1458,1346,835;HRMS(positive-SIMS), m/z:711.3730(M+1)(计算值C37H57N9S2:711.3734)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-((3-苯烯丙基)氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDf):淡黄色粉末,mp 115.6~117.0 ℃,收率68.3%。1H NMR(CDCl3,500 MHz), δ:10.41(s,1H),7.60~7.58(m,2H),7.45~7.41(m,3H),7.33(d, J=16.0 Hz,1H),7.15(dd, J=9.4 Hz,16.0 Hz,1H),5.13(s,2H),2.88(s,4H),2.77(t, J=7.7 Hz,2H),1.77~1.73(m,2H),1.39~1.35(m,2H),1.31~1.26(m,14H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.55,161.57,150.86,137.21,135.24,134.16,128.64,128.57,127.92,126.37,68.88,50.46,31.86,29.57,29.05,26.15,25.04,22.68,14.08;IR(KBr), σ/cm-1:3433,2922,2844,1587,1512,1458,1346,835;HRMS(positive-SIMS), m/z:879.5610(M+1)(计算值C37H57N9S2:879.5612)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-二茂铁基-5-戊基-1 H-1,2,4-三唑-3(4 H)-硫酮)(PTSDg):橘黄色粉末,mp 186.8~188.2 ℃,收率75.6%。1H NMR(CDCl3,500 MHz), δ:9.71(s,1H),5.11(s,2H),4.76(t, J=1.8 Hz,2H),4.57(t, J=1.8 Hz,2H),4.35(s,5H),2.86(s,4H),2.79(t, J=7.6 Hz,2H),1.76~1.72(m,2H),1.39~1.36(m,4H),0.92~0.89(m,3H);13C NMR(CDCl3,125 MHz), δ:162.53,161.55,150.82,75.57,71.95,70.42,69.01,68.86,50.46,31.23,25.81,25.00,22.16,13.87;IR(KBr), σ/cm-1:3433,2922,2844,1675,1587,1414,1346,1276,1185,835;HRMS(positive-SIMS), m/z:875.2749(M+1)(计算值C37H57N9S2:875.2746)。

2,2'-(哌嗪-1,4-二基双(亚甲基))双(4-二茂铁基-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮)(UTSDg):橘黄色粉末,mp 207.4~208.5 ℃,收率79.6%。1H NMR(CDCl3,500 MHz), δ:9.71(s,1H),5.11(s,2H),4.76(t, J=1.8 Hz,2H),4.57(t, J=1.8 Hz,2H),4.35(s,5H),2.86(s,4H),1.77~1.73(m,2H),1.39~1.35(m,2H),1.31~1.26(m,14H),0.92(t, J=7.0 Hz,3H);13C NMR(CDCl3,125 MHz), δ:162.53,161.55,150.82,75.57,71.95,70.42,69.01,68.86,50.46,31.83,29.54,29.03,26.16,25.04,22.65,14.08;IR(KBr), σ/cm-1:3426,3108,2922,2844,1605,1414,1286,1176,1085,835,503;HRMS(positive-SIMS), m/z:1043.4629(M+1)(计算值C37H57N9S2:1043.4624)。

1.3 生物活性测试

1.3.1 植物生长调节活性和除草活性 本文利用黄瓜子叶生根法测定目标化合物的细胞分裂素活性,小麦芽鞘法测定目标化合物的细胞生长素活性,利用抑制稗草生根的方法测试目标化合物的除草活性。 测试方法参照文献[16-17]进行。

1.3.2 CDC25B抑制活性 选择抑制率>50%的化合物进行复筛,测试样品浓度为5 mg/L时的抑制活性,得出抑制活性剂量依赖关系,即IC50值。 IC50值通过样品活性对样品浓度进行非线性拟合得到。 筛选实验参照文献[18-20]方法进行。

2 结果与讨论
2.1 目标化合物合成与表征

运用多组分合成法,高效、简捷的将脂肪基、1,2,4-三唑、芳香基团和吗啉(或哌嗪)等活性基团构筑在1个分子中,通过IR、1H NMR、13C NMR和HRMS等分析方法对目标化合物进行了表征。 IR谱图中,在3100、1600~1450 cm-1左右范围的IR信号可以证明所有目标分子结构中存在芳香环;1650和1500 cm-1左右出现C=N和C=C的吸收峰,在1280 cm-1左右出现C=S的吸收峰,在1150和1100 cm-1左右的峰分别为C—O和C—N的吸收峰,初步表明1,2,4-三唑、芳香基团和吗啉(或哌嗪)等结构的存在。1H NMR谱图中, HC=N上的质子信号在 δ 10.0左右处,在 δ 7.00~8.00处为芳环的质子信号,表明希夫碱结构成功构筑于分子中,在 δ 5.2左右处出现的为—NCH2N—中亚甲基的质子信号,吗啉环的质子信号在 δ 2.8和 δ 3.7左右, N-甲基哌嗪环的质子信号在 δ 2.4和 δ 2.9左右,2.3左右为—NCH3的质子信号,哌嗪环的质子信号在 δ 5.2左右,说明吗啉和哌嗪成功与1,2,4-三唑通过亚甲基对接。13C NMR谱图中,在 δ 110~170范围内出现的信号峰为芳香环的碳信号,在 δ 60~80范围内出现二茂铁的碳信号峰,在 δ 45~67范围内出现吗啉、 N-甲基哌嗪及哌嗪的碳信号峰,在 δ 21~32范围内出现脂肪基的碳信号峰;HRMS谱图中,所有的化合物均出现了[M+1]+峰,上述结构分析表明,通过本文方法成功合成了目标分子。

2.2 活性测试

2.2.1 植物生长调节活性和除草活性 植物生长调节活性和除草活性测试结果如表1所示,表中的计算结果均为正值,表明具有促进作用。 其中三唑酮(Triadimefon,Tri)和 N-羟基- N-异丙基草酰胺( N-Hydroxy- N-isopropyloxamate,IPOHA)分别作为细胞分裂素活性测试和除草活性测试的参照物。

表1 目标化合物对植物生长调节活性及除草活性 a Table 1 Plant growth regulating activity and herbicidal activity of the target compounds a

利用离体黄瓜子叶生根的方法测定细胞分裂活性,将离体子叶在浓度为10 mg/L的溶液中进行培养,大多数化合物都表现出优良的促进作用,其中15个目标化合物效果表现为A级。 利用小麦芽鞘法测定生长素活性,将离体子叶在浓度为10 mg/L的溶液中进行培养,大多数化合物都表现出良好的促进作用。 在测试浓度下,除草实验结果表明:15个化合物的除草活性优于阳性参照物IPOHA,表现出良好的除草效果。

对比脂肪基不同、其它结构相同的目标分子的作用效果发现:对于单三唑化合物(PTSP、UTSP、PTSM和UTSM),多数5-脂肪基含较多碳原子数时,目标分子具有更好的生物活性,这是由于脂肪碳链增加时,改善了分子的脂溶性,使生物活性提高呈现出较好的作用效果,其中UTSMb在细胞分裂活性中促进效果最佳达71.5%,UTSMa在生长素活性测试中促进效果最好达43.9%,所有目标分子在除草活性中均具有优良的活性;对于双三唑化合物(PTSD和UTSD),5-脂肪基含较多碳原子数的分子同样表现出更好的活性,其中UTSDe在细胞分裂活性中,促进效果最佳达59.6%,UTSDd在生长素活性中促进效果最好达34.9%,UTSDf在除草活性中表现出极佳的活性,作用率高达86.9%,两类分子中哌嗪和吗啉的引入均产生优良活性,区别不大。 研究还发现,当在4-位点上引入吡啶、呋喃和二茂铁等药效基团时,目标分子的生物活性均有不同程度的改善,这为新药创制药效基团的有效引入提供了重要的参考。比较单三唑、双三唑两类化合物,双三唑结构分子的活性未达到之前活性叠加预想,这可能是由于其较大的空间结构,产生一定位阻使活性未能显著提升。

以正钒酸为阳性参照物。 在目标分子浓度为5 mg/L的条件下,针对CDC25B的抑制活性进行初筛测试,然后选择抑制率大于50%的样品进行复筛,测得其IC50值。 结果显示:含有十一烷基、对甲氧基苯及吗啉结构的目标分子UTSMa具有优良的CDC25B抑制活性,其抑制率高达(94.90±2.07)%,IC50值达(1.79±0.28) mg/L,低于阳性参照物正钒酸钠[(1.86±0.24) mg/L],表明UTSMa有望成为潜在的CDC25B抑制剂。

3 结 论

设计合成了22种新型曼尼希衍生物,其中15种目标化合物具有较高的细胞分裂素活性,其中最高促进率达83.0%,表明该类新型结构分子有望成为植物生长调节剂;15种目标分子具有优良的除草活性,除草率高达86.9%,有望成为优良的除草剂。 2-(吗啉代甲基)-(4-甲氧基苯烯基氨基)-5-十一烷基-1 H-1,2,4-三唑-3(4 H)-硫酮(UTSMa)具有优良的细胞周期分裂蛋白25B(CDC25B)抑制活性,IC50值达(1.79±0.28) mg/L,优于阳性参照物正钒酸钠,有望成为作为肿瘤治疗的药物先导物。

致谢 活性筛选实验由国家新药筛选中心协助测试,在此对他们的帮助表示诚挚的谢意。

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