1-取代-4-[5-(4-取代苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪類衍生物的合成及其抑菌活性*

吳 琴,王貞超,魏 學,薛 偉

(1.貴州大學 精細化工研究開發中心 教育部綠色農藥和生物工程重點實驗室，貴州 貴陽 550025；2.貴州理工學院 制藥工程學院,貴州 貴陽 550003)

·研究論文·

1-取代-4-[5-(4-取代苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪類衍生物的合成及其抑菌活性*

吳 琴1,2,王貞超1,魏 學1,薛 偉1

(1.貴州大學 精細化工研究開發中心 教育部綠色農藥和生物工程重點實驗室，貴州 貴陽 550025；2.貴州理工學院 制藥工程學院,貴州 貴陽 550003)

根據活性亞結構拼接原理，將1,3,4-噻二唑環和哌嗪環通過磺?；鶚蚪?，設計并合成了16個新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪類衍生物(4a～4p)，其結構經1H NMR，13C NMR，IR和元素分析表征?？疾炝巳軇?、縛酸劑和反應溫度對1-甲基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4a)產率的影響。合成4a的最佳反應條件為:乙腈為溶劑，三乙胺為縛酸劑，于25℃反應5h,產率75%。采用生長速率法研究了4a～4p對小麥赤霉菌、蘋果腐爛病菌和辣椒枯萎病菌的抑制活性。結果表明：在用藥量為50μg·mL-1時，1-(4-氟芐基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4d)和1-丙炔基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4n)對三種病菌均具有較好的抑制活性。

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、殺蟲、抗真菌和抗病毒等多種生物活性[1-5]。如日本石原公司開發的殺菌劑氰霜唑，對卵菌綱類病害具有良好的抑制活性；美國Dow Agrosciences公司開發的除草劑雙氟磺草胺，主要用于苗后防除冬小麥和玉米田闊葉雜草。尋找新型結構的磺酰胺類化合物成為藥物開發的一個重要方向。

哌嗪類化合物也顯示了廣譜的生物活性，在抗真菌、抗病毒、抗腫瘤、殺蟲和除草等領域中發揮著重要作用[6-8]。胡國強等[9]在合成系列稠雜環的新化合物時發現，和母體結構相比，極性堿性哌嗪基的引入有利于提高化合物的活性。1,3,4-噻二唑類化合物具有獨特的抗真菌、病毒、殺蟲、除草和抗氧化等活性[10-13]，如葉青雙能有效防治水稻白葉枯??；諾華公司開發的除草劑Fluthiacetmethy，能完全控制玉米和馬鈴薯中的闊葉雜草。

本課題組在前期工作[14-18]中合成了含1,3,4-噻二唑雜環的硫醚、亞砜和砜類化合物，發現其中部分化合物表現出較好的生物活性。在此基礎上，通過引入磺酰胺基團，進一步進行結構改造，有望得到較高抑菌活性的新化合物。為此，本文根據活性亞結構拼接原理，將1,3,4-噻二唑環和哌嗪環通過磺?；鶚蚪?，設計并合成了16個新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪類衍生物(4a～4p，Scheme 1)，其結構經1H NMR，13C NMR，IR和元素分析表征。并采用生長速率法研究了4a～4p對小麥赤霉菌，蘋果腐爛病菌和辣椒枯萎病菌的抑制活性。

1 實驗部分

1．1 儀器與試劑

XT-5型顯微熔點儀(溫度未校正)；JEOL-ECX 500MHz型核磁共振儀(DMSO-d6為溶劑，TMS為內標)；IR Prestige-21型紅外光譜儀(KBr壓片)；Elementar Vario-III型元素分析儀。

5-(4-硝基苯基)-2-巰基-1，3,4-噻二唑(1a)和5-(2，4-二氯苯基)-2-巰基-1，3,4-噻二唑(1i)按文獻[17]方法合成；其余所用試劑均為分析純或化學純。

1．2 合成

(1)2a和2i的合成

在反應瓶中依次加入1a2.0mmol，1,2-二氯乙烷12mL和水6mL，冰鹽浴冷卻，攪拌下加入濃鹽酸3mL，于0℃通入氯氣15min(反應體系呈黃綠色)?？焖俜忠汉竺撊?，有機相用無水硫酸鎂干燥得淡黃色固體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℃。

用類似的方法合成白色固體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

在反應瓶中依次加入單取代哌嗪3a～3h1.0mmol和無水乙腈5mL，攪拌使其溶解；緩慢(15min)滴加2a(1.0mmol)的無水乙腈(10mL)溶液；滴加三乙胺0.2mL，滴畢，于25℃反應5h。抽濾，濾餅用無水乙腈洗滌，干燥后用混合溶劑[V(DMF)∶V(EtOH)=1∶2]重結晶得4a～4h。

用2i替代2a，用類似的方法合成4i～4p。

1-甲基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4a)：黃色晶體，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?；鵠哌嗪(4b)：白色晶體，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-芐基-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4c)：淡黃色晶體，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-氟芐基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4d):白色晶體，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-硝基芐基)-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4e):白色晶體，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?；鵠哌嗪(4f)：淡黃色針狀晶體，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?；鵠哌嗪(4g):黃色晶體，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?；鵠哌嗪(4h)：白色晶體，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?；鵠哌嗪(4i)：白色晶體，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?；鵠哌嗪(4j):白色晶體，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-芐基-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4k):白色晶體，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-氟芐基)-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4l):白色晶體，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-硝基芐基)-4-[5-(2,4-二氯苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪(4m):白色晶體，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?；鵠哌嗪(4n):黃色針狀晶體，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?；鵠哌嗪(4o):白色晶體，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?；鵠哌嗪(4p):白色晶體，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 抑菌活性測定

以多菌靈為陽性對照組，采用生長速率法[19]，在用藥量為50μg·mL-1下測試4a～4p對小麥赤霉菌(G.zeae)，蘋果腐爛病菌(C.mandshurica)和辣椒枯萎病菌(F.oxysporum)的抑制活性。

2 結果與討論

2．1 合成

(1)2的合成

在2的合成中發現溶劑對氯氧化反應有較大影響。為此，考察了溶劑對2i收率的影響，結果見表 1。由表1可見，以A和B為溶劑時，收率較低;以C為溶劑時，當體積比為4∶2∶1時，收率較高(52%)。合成2i的最佳溶劑為C,即V(ClCH2CH2Cl)∶V(H2O)∶V(HCl)=4∶2∶1。

(2)4的合成

以合成4a為模板，考察溶劑、縛酸劑和反應溫度對4a收率的影響，結果見表2。由表2可見，當溫度、反應時間和縛酸劑不變，選用乙腈為溶劑時收率最高；當溫度、反應時間和溶劑不變時，以三乙胺為縛酸劑時收率最高，以吡啶為縛酸劑時，收率僅46%。其可能原因是吡啶鹽對4a有一定的溶解作用；當以乙腈為溶劑，三乙胺為縛酸劑，反應時間為5h時，隨著溫度的升高，收率有所提高；溫度升至35℃時，收率反而降低。由此可見，合成4a的最佳條件為：乙腈為溶劑，三乙胺為縛酸劑，于25℃反應5h，收率75%。

表1 溶劑對合成2i的影響*Table1 Effect of solvent on synthesizing 2i

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

表2 反應條件對合成4a的影響*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

續表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的抑菌活性見表3。由表3可見，4a～4p對三種菌均有一定抑菌活性，其中4d和4n對三種病菌的抑制活性較好,但均次于陽性對照藥多菌錄靈。

3 結論

設計并合成了16個新型的1-取代-4-[5-(4-硝基苯基)-1,3,4-噻二唑-2-磺?；鵠哌嗪類衍生物(4a～4p)。合成4a的最佳反應條件為:乙腈為溶劑，三乙胺為縛酸劑，于25℃反應5h,收率75%。

抑菌活性測試結果表明：在用藥量為50μg·mL-1時，4d和 4n對小麥赤霉菌，蘋果腐爛病菌和辣椒枯萎病菌均有較好的抑制活性。

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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

國家自然科學基金資助項目(20762002)；國家十二五科技支撐計劃資助項目(2011BAE06B04-09)

吳琴(1974-)，女，漢族，貴州貴陽人，副教授，主要從事新農藥設計與合成的研究。E-mail:wuqin1974@163.com

O626.25；O626.32

A

1005-1511(2014)04-0429-06