1-取代-4-[5-(4-取代苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪类衍生物的合成及其抑菌活性*

吴 琴,王贞超,魏 学,薛 伟

(1.贵州大学 精细化工研究开发中心 教育部绿色农药和生物工程重点实验室，贵州 贵阳 550025；2.贵州理工学院 制药工程学院,贵州 贵阳 550003)

·研究论文·

1-取代-4-[5-(4-取代苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪类衍生物的合成及其抑菌活性*

吴 琴1,2,王贞超1,魏 学1,薛 伟1

(1.贵州大学 精细化工研究开发中心 教育部绿色农药和生物工程重点实验室，贵州 贵阳 550025；2.贵州理工学院 制药工程学院,贵州 贵阳 550003)

根据活性亚结构拼接原理，将1,3,4-噻二唑环和哌嗪环通过磺酰基桥接，设计并合成了16个新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪类衍生物(4a～4p)，其结构经1H NMR，13C NMR，IR和元素分析表征。考察了溶剂、缚酸剂和反应温度对1-甲基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4a)产率的影响。合成4a的最佳反应条件为:乙腈为溶剂，三乙胺为缚酸剂，于25℃反应5h,产率75%。采用生长速率法研究了4a～4p对小麦赤霉菌、苹果腐烂病菌和辣椒枯萎病菌的抑制活性。结果表明：在用药量为50μg·mL-1时，1-(4-氟苄基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4d)和1-丙炔基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4n)对三种病菌均具有较好的抑制活性。

1,3,4-噻二唑；哌嗪；磺胺；合成；抑菌活性

磺酰胺衍生物具有抗菌、杀虫、抗真菌和抗病毒等多种生物活性[1-5]。如日本石原公司开发的杀菌剂氰霜唑，对卵菌纲类病害具有良好的抑制活性；美国Dow Agrosciences公司开发的除草剂双氟磺草胺，主要用于苗后防除冬小麦和玉米田阔叶杂草。寻找新型结构的磺酰胺类化合物成为药物开发的一个重要方向。

哌嗪类化合物也显示了广谱的生物活性，在抗真菌、抗病毒、抗肿瘤、杀虫和除草等领域中发挥着重要作用[6-8]。胡国强等[9]在合成系列稠杂环的新化合物时发现，和母体结构相比，极性碱性哌嗪基的引入有利于提高化合物的活性。1,3,4-噻二唑类化合物具有独特的抗真菌、病毒、杀虫、除草和抗氧化等活性[10-13]，如叶青双能有效防治水稻白叶枯病；诺华公司开发的除草剂Fluthiacetmethy，能完全控制玉米和马铃薯中的阔叶杂草。

本课题组在前期工作[14-18]中合成了含1,3,4-噻二唑杂环的硫醚、亚砜和砜类化合物，发现其中部分化合物表现出较好的生物活性。在此基础上，通过引入磺酰胺基团，进一步进行结构改造，有望得到较高抑菌活性的新化合物。为此，本文根据活性亚结构拼接原理，将1,3,4-噻二唑环和哌嗪环通过磺酰基桥接，设计并合成了16个新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪类衍生物(4a～4p，Scheme 1)，其结构经1H NMR，13C NMR，IR和元素分析表征。并采用生长速率法研究了4a～4p对小麦赤霉菌，苹果腐烂病菌和辣椒枯萎病菌的抑制活性。

1 实验部分

1．1 仪器与试剂

XT-5型显微熔点仪(温度未校正)；JEOL-ECX 500MHz型核磁共振仪(DMSO-d6为溶剂，TMS为内标)；IR Prestige-21型红外光谱仪(KBr压片)；Elementar Vario-III型元素分析仪。

5-(4-硝基苯基)-2-巯基-1，3,4-噻二唑(1a)和5-(2，4-二氯苯基)-2-巯基-1，3,4-噻二唑(1i)按文献[17]方法合成；其余所用试剂均为分析纯或化学纯。

1．2 合成

(1)2a和2i的合成

在反应瓶中依次加入1a2.0mmol，1,2-二氯乙烷12mL和水6mL，冰盐浴冷却，搅拌下加入浓盐酸3mL，于0℃通入氯气15min(反应体系呈黄绿色)。快速分液后脱溶，有机相用无水硫酸镁干燥得淡黄色固体5-(4-硝基苯基)-1，3,4-噻二唑-2-磺酰氯(2a)0.38g，收率63%，m.p.123℃～125℃。

用类似的方法合成白色固体5-(2，4-二氯苯基)-1，3,4-噻二唑-2-磺酰氯(2i)0.32g，收率50%,m.p.92℃～95℃。

(2)4a～4p的合成通法

在反应瓶中依次加入单取代哌嗪3a～3h1.0mmol和无水乙腈5mL，搅拌使其溶解；缓慢(15min)滴加2a(1.0mmol)的无水乙腈(10mL)溶液；滴加三乙胺0.2mL，滴毕，于25℃反应5h。抽滤，滤饼用无水乙腈洗涤，干燥后用混合溶剂[V(DMF)∶V(EtOH)=1∶2]重结晶得4a～4h。

用2i替代2a，用类似的方法合成4i～4p。

1-甲基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4a)：黄色晶体，收率75%，m.p.203℃～205℃;1H NMRδ:8.24(d,J=10.00Hz,2H,ArH),8.36(d,J=10.00Hz,2H,ArH),2.49～2.51(m,8H,a,b,c,d-H),2.23(s,3H,CH3);13C NMR(125MHz,下同)δ:170.7,166.2,149.9,134.5,130.3,125.2,53.9,46.3,45.6;IRν:3111,2941,2910,2796,1519,1340,1319,1172,1087,983,604,592,518cm-1;Anal.calcd for C13H15N5O4S2:C 42.27,H 4.09,N 18.96;found C 42.10,H 3.79,N 19.31。

1-乙氧羰基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4b)：白色晶体，收率71%，m.p.212℃～214℃;1H NMRδ:8.24～8.43(m,4H,ArH),4.01(q,J=7.45Hz,2H,CH2in Et),3.34～3.35(m,8H,a,b,c,d-H),1.15(t,J=6.85Hz,3H,CH3in Et);13C NMRδ:170.9,169.1,165.8,155.5,154.8,149.9,149.6,134.9,134.5,61.6,46.2,43.0,15.0;IRν:3107,3076,1683,1597,1512,1489,1373,1323,1166cm-1;Anal.calcd for C15H17N5O6S2：C 42.15,H 4.01,N 16.38;found C 42.45,H 4.40,N 16.08。

1-苄基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4c)：淡黄色晶体，收率68%，m.p.223℃～225℃;1H NMRδ:8.42(d,J=10.00Hz,2H,ArH),8.36(d,J=10.00Hz,2H,ArH),7.22～7.32(m,5H,ArH),3.51(s,2H,CH2in Bn),3.32～3.35(m,8H,a,b,c,d-H)；13C NMRδ:170.8,166.1,149.9,138.1,134.5,130.3,129.3,128.8,127.6,125.1,61.8,51.9,46.7;IRν:3109,2916,1699,1520，1361,1338,1172,1116,983,854,721,592cm-1;Anal.calcd for C19H19N5O4S:C 51.22,H 4.30,N 15.72;found C 51.62,H 4.26,N 15.42。

1-(4-氟苄基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4d):白色晶体，收率49%,m.p.203℃～205℃;1H NMRδ:8.39(d,J=10.00Hz,ArH),8.18(d,J=10.00Hz,2H,ArH),6.97～7.26(m,4H,ArH),3.52(s,2H,1′-Η),2.69～3.51(m,8H,a,b,c,d-H);13C NMRδ:169.7,166.8,149.9,134.4,130.7,129.3,124.8,115.5,115.3,61.7,51.9,46.7;IRν:3113,2868,2837,2777,1598,1508,1373,1340,1319,1178,1126,948,852,727,592,549cm-1;Anal.calcd for C19H18N5O4S2F:C 51.22,H 4.30,N 15.72;found C 51.62,H 4.26,N 15.42。

1-(4-硝基苄基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4e):白色晶体，收率65%,m.p.232℃～234℃;1H NMRδ:8.40(d,J=10.00Hz,2H,ArH),8.17～8.19(m,4H,ArH),7.49(d,J=10.00Hz,2H,ArH),2.63～3.66(m,10H,a,b,c,d,1′-H);13C NMRδ:170.8,169.9,166.1,150.0,134.4,130.3,125.1,124.0,114.9;IRν:3109,2927,1598,1520,1456，1367,1346,1174,954,852,723,590cm-1;Anal.calcd for C19H18N6O6S2:C 46.52,H 3.70,N 16.13;found C 46.76,H 3.64,N 16.51。

1-丙炔基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4f)：淡黄色针状晶体，收率58%，m.p.208℃～211℃;1H NMRδ:8.39(d,J=10.00Hz,2H,ArH),8.18(d,J=10.00Hz,2H,ArH),3.56(t,J=10.00Hz,4H,a,b,c,d-H),3.36(s,2H,1′-H),2.72(t,J=10.00Hz,4H,a,b,c,d-H),2.29(s,1H,3′-H);13C NMRδ:170.8,166.2,149.9,134.4,130.3,125.1，50.5,46.2,46.0;IRν:3107,2931,2823,1640,1584,1348,1315,1126,956,854,729,590cm-1;Anal.calcd for C15H15N5O4S2:C 45.79,H 3.84,N 17.80;found C 45.98,H 3.74,N 17.56。

1-(4-喹唑啉基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4g):黄色晶体，收率67%,m.p.234℃～236℃;1H NMRδ:8.78(s,1H,1-H),8.40(d,J=10.00Hz,2H,ArH),8.19(d,J=10.00Hz,2H,ArH),7.51～7.96(m,4H,3′,4′,5′,6′-H),3.94～3.76(m,8H,a,b,c,d-H);13C NMRδ:170.9,166.0,164.2,153.9,151.6,149.9,134.4,133.5,130.2,128.5,126.5,125.7,125.1,116.3,48.9,46.3;IRν：3109,2916,2891,1568,1429,1377,1328,1174,945,854,773,688,592,528cm-1;Anal.calcd for C20H17N7O4S2:C 49.68,H 3.54,N 20.28;found C 49.74,H 3.86,N 19.98。

1-[(2-氯噻唑-4-基)甲基]-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4h)：白色晶体，收率68%，m.p.229℃～231℃;1H NMRδ:8.42(d,J=10.00Hz,2H,ArH),8.19(d,J=10.00Hz,2H,ArH),7.26(s,1H,3′-H),3.71(s,2H,4′-H),3.54～2.66(m,8H,a,b,c,d-H);13C NMRδ:170.9,166.1,150.0,134.4,130.3,125.1;IRν：3107,2914,2368,1597，1520,1450，1353,1332,1176,956,852,725,686,509cm-1;Anal.calcd for C16H15N6O4S2Cl：C 39.46,H 3.10,N 17.26;found C 39.25,H 3.02,N 17.01。

1-甲基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4i)：白色晶体，收率54%，m.p.152℃～154℃;1H NMRδ:7.45～8.40(m,3H,ArH),2.49～2.51(m,8H,a,b,c,d-H),2.23(s,3H,CH3);13C NMRδ:166.4,166.3,138.6,133.6,132.1,130.7,128.3,126.5,54.1,46.5,45.9;IRν:3089,2935,2800,1640,1456,1373,1352,1176,1155,958,729,619,595cm-1;Anal.calcd for C13H14N5O2S2Cl2:C 39.70,H 3.59，N 14.24;found C 39.30,H 3.79,N 14.64。

1-乙氧羰基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4j):白色晶体，收率63%,m.p.139℃～141℃;1H NMRδ:8.38(d,J=8.55Hz,ArH),7.60(s,1H,ArH),7.45(d,J=8.6Hz,1H,ArH),4.11(q,J=5.92Hz,2H,CH2in Et),3,49～3,65(m,8H,a,b,c,d-H),1.25(t,J=6.85Hz,3H,CH3in Et);13C NMRδ:166.6,155.1,138.7,133.6,132.0,130.7,128.4,126.3,62.0,46.5,14.6;IRν:3080,2987,2870,1690,1471,1382,1365,1163,952,862,727,596cm-1;Anal.calcd for C15H16N4O4S2Cl2:C 39.92,H 3.57,N 12.41;found C 39.67,H 3.49,N 12.18。

1-苄基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4k):白色晶体，收率56%,m.p.125℃～127℃;1H NMRδ:8.13(d,J=10.00Hz,1H,ArH),7.47(d,J=10.00Hz,1H,ArH),7.32～7.34(m,5H,ArH),7.26～7.30(m,1H,ArH),3.62(t,J=10.00Hz,4H,a,b,c,d-H),3.58(s,2H,CH2in Bn),2.59(t,J=10.00Hz,4H,a,b,c,d-H);13C NMRδ:173.5,152.6,131.9,131.2,130.2,129.2,128.6,128.5,127.8,127.5,63.0,52.1,49.8;IRν:3089,2935,2800,1640,1456,1373,1352,1176,1155,958,729,619,595cm-1;Anal.calcd for C19H18N4O2S2Cl2:C 48.62,H 3.87,N 11.94;found C 48.42,H 3.69,N 11.58。

1-(4-氟苄基)-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4l):白色晶体，收率72%,m.p.140℃～142℃;1H NMRδ:8.13(d,J=10.00Hz,1H,ArH),7.47(d,J=10.00Hz,1H,ArH)),7.32～7.33(m,1H,ArH),7.03～7.26(m,4H,ArH),3.61(t,J=10.00Hz,4H,a,b,c,d-H),3.53(s,2H,1′-H),2.58(t,J=10.00Hz,4H,a,b,c,d-H);13C NMRδ:168.9,135.9,131.9,131.2,130.7,130.1,127.7,115.4,115.2,62.1,51.8,49.5;IRν:3111,2956,2850,1640,1500,1444,1375,1317,1240,1103,906,806,596,503cm-1;Anal.calcd for C19H17N4O2S2Cl2:C 46.82,H 3.52,N 11.50;found C 46.55,H 3.75,N 11.39。

1-(4-硝基苄基)-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4m):白色晶体，收率79%,m.p.163℃～165℃;1H NMRδ:8.29～8.34(m,3H,ArH),7.72～8.03(m,4H,ArH),3.25～3.97(m,10H,a,b,c,d,1′-H);13C NMRδ:166.6,166.5,147.4,145.4,133.6,132.0,130.7,129.4,128.4,126.4,123.7,61.6,52.2,46.6;IRν:3074,2937,2912,2819,1606,1587,1501,1361,1328,1168,1109,954,729,707cm-1;Anal.calcd for C19H17N5O4S2Cl2:C 44.36,H 3.33,N 13.61;found C 44.58,H 3.03,N 13.84。

1-丙炔基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4n):黄色针状晶体，收率71%,m.p.137℃～139℃;1H NMRδ:8.39(d,J=10.00Hz,1H,ArH),7.61(d,J=10.00Hz,1H,ArH),7.46～7.48(m,1H,ArH),3.53(t,J=10.00Hz,4H,a,b,c,d-H),3.35(s,2H,1′-H),2.71(t,J=10.00Hz,4H,a,b,c,d-H),2.28(s,1H,3′-H);13C NMRδ:166.4,166.3,138.6,133.5,132.0,130.7,128.3,126.4,77.8,73.9,50.9,46.7,46.5;IRν：3084,2947,2819,1585,1456,1357,1317,1118,950,831,727,634,590,466cm-1;Anal.calcd for C15H14N4O2S2Cl2:C 43.17,H 3.38,N 13.42;found C 43.34,H 3.45,N 13.27。

1-(4-喹唑啉基)-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4o):白色晶体，收率64%,m.p.104℃～107℃;1H NMRδ:8.77(s,1H,1-H),7.62～8.41(m,4H,3′,4′,5′,6′-H),7.46～7.50(m,3H,ArH),3.73～3.92(m,8H,a,b,c,d-H);13C NMRδ:153.9,151.7,137.9,133.5,132.9,130.9,129.0,128.6,126.5,125.7,116.3,48.9,46.3;IRν:3113,2969,2843,1610,1570,1498,1370,1340,1263,1140,964,827,775cm-1;Anal.calcd for C20H16N6O2S2Cl2:C 47.34,H 3.18,N 16.56;found C 46.99,H 3.46,N 16.35。

1-[(2-氯噻唑-4-基)甲基]-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪(4p):白色晶体，收率72%,m.p.139℃～141℃;1H NMRδ:7.71～8.32(m,3H,ArH),7.62(s,1H,3′-H),3.57(s,2H,4′-H),2.47～3.34(m,8H,a,b,c,d-H);13C NMRδ:167.1,167.0,166.0,137.9,133.6,133.5,132.9,130.9,129.0,126.7,51.2;IRν:3078,2937,2829,1585,1456,1363,1334,1172,956,798,725,623,590,553cm-1;Anal.calcd for C16H14N5O2S3Cl3:C 37.62,H 2.76,N 13.71;found C 37.52,H 2.81,N 13.54。

1．3 抑菌活性测定

以多菌灵为阳性对照组，采用生长速率法[19]，在用药量为50μg·mL-1下测试4a～4p对小麦赤霉菌(G.zeae)，苹果腐烂病菌(C.mandshurica)和辣椒枯萎病菌(F.oxysporum)的抑制活性。

2 结果与讨论

2．1 合成

(1)2的合成

在2的合成中发现溶剂对氯氧化反应有较大影响。为此，考察了溶剂对2i收率的影响，结果见表 1。由表1可见，以A和B为溶剂时，收率较低;以C为溶剂时，当体积比为4∶2∶1时，收率较高(52%)。合成2i的最佳溶剂为C,即V(ClCH2CH2Cl)∶V(H2O)∶V(HCl)=4∶2∶1。

(2)4的合成

以合成4a为模板，考察溶剂、缚酸剂和反应温度对4a收率的影响，结果见表2。由表2可见，当温度、反应时间和缚酸剂不变，选用乙腈为溶剂时收率最高；当温度、反应时间和溶剂不变时，以三乙胺为缚酸剂时收率最高，以吡啶为缚酸剂时，收率仅46%。其可能原因是吡啶盐对4a有一定的溶解作用；当以乙腈为溶剂，三乙胺为缚酸剂，反应时间为5h时，随着温度的升高，收率有所提高；温度升至35℃时，收率反而降低。由此可见，合成4a的最佳条件为：乙腈为溶剂，三乙胺为缚酸剂，于25℃反应5h，收率75%。

表1 溶剂对合成2i的影响*Table1 Effect of solvent on synthesizing 2i

*solvent volume 20mL，other reaction conditions as same as 1.2(1)

表2 反应条件对合成4a的影响*Table2 Effect of reaction conditions on synthesizing 4a

*other reaction conditions as same as 1.2(2)

表3 4a～4p的抑菌活性Table3 Antibacterial activities of 4a～4p

续表3

CompInhibitionratio/%G．zeaeC．mandshuricaF．oxysporum4l6．71±2．2828．34±1．1410．37±1．414m10．06±1．1143．12±1．3413．11±1．474n57．13±2．2442．80±1．5146．04±1．424o27．13±2．2222．80±1．5041．04±1．404p11．89±0．9114．01±2．2010．67±1．19A100100100

A=Carbendazim

2．2 抑菌活性

4a～4p的抑菌活性见表3。由表3可见，4a～4p对三种菌均有一定抑菌活性，其中4d和4n对三种病菌的抑制活性较好,但均次于阳性对照药多菌录灵。

3 结论

设计并合成了16个新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺酰基]哌嗪类衍生物(4a～4p)。合成4a的最佳反应条件为:乙腈为溶剂，三乙胺为缚酸剂，于25℃反应5h,收率75%。

抑菌活性测试结果表明：在用药量为50μg·mL-1时，4d和 4n对小麦赤霉菌，苹果腐烂病菌和辣椒枯萎病菌均有较好的抑制活性。

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SynthesisandAntibacterialActivitiesof1-Substituted-4-[5-(4-sub-stitutedphenyl)-1,3,4-thiadiazol-2-sulfonyl]piperazineDerivatives

WU Qin1,2, WANG Zhen-chao1, WEI Xue1, XUE Wei1

(1.Key Laboratory of Green Pesticide and Bioengineering,Ministry of Education,Research and Development Center for Fine Chemicals,Guizhou University,Guiyang 550025,China；2.School of Pharmaceutical Engineering,Guizhou Institute of Technology,Guiyang 550003,China)

Sixteen novel 1-substituted-4-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine derivatives(4a～4p)were designed and synthesized by connection reaction of 1,3,4-thiadiazol withN-substitued piperazine.The structures were characterized by1H NMR,13C NMR,IR and elemental analysis.Effects of the solvent,acid acceptor and reaction temperature on the yield of 1-methyl-4-[5-(4-nitrophenyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine(4a)were investigated.The optimum reaction conditions for synthesizing4awith the yield of 75% at 25℃ for 5h were as follows:acetonitrile was solvent and triethylamine was acid acceptor.The antibacterial activities of4a～4pagainstG.zeae,C.mandshuricaandF.oxysporumwere investigated by growth rate method.The results indicated that 1-methyl-4-[5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine(4d)and 1-methyl-4-[5-(4-propinyl)-1,3,4-thiadiazol-2-sulfonyl]piperazine(4n)exhibited better antibacterial activities at 50μg·mL-1.

1,3,4-thiadiazol；piperazine;sulfonamide;synthesis;antibacterial activity

2014-01-24;

2014-03-12

国家自然科学基金资助项目(20762002)；国家十二五科技支撑计划资助项目(2011BAE06B04-09)

吴琴(1974-)，女，汉族，贵州贵阳人，副教授，主要从事新农药设计与合成的研究。E-mail:wuqin1974@163.com

O626.25；O626.32

A

1005-1511(2014)04-0429-06