新型含2,4-二氯苯基的1,2,4-三唑喹唑啉衍生物的合成及抑菌活性

張貴強(qiáng), 郭晴晴, 易君明, 趙廷淵, 王 梅, 邢林娜

(興義民族師范學(xué)院 貴州省化學(xué)合成及環(huán)境污染控制和修復(fù)技術(shù)特色重點(diǎn)實(shí)驗(yàn)室，貴州 興義 562400)

柑橘潰瘍病、煙草青枯病、水稻百葉枯病是常見的農(nóng)作物疾病，對(duì)農(nóng)作物的質(zhì)量和產(chǎn)量造成了不利影響，導(dǎo)致了嚴(yán)重的經(jīng)濟(jì)損失。現(xiàn)有農(nóng)藥抑菌劑受耐藥性影響，防治效果不太理想。開發(fā)高效、低毒、環(huán)境友好型的新型殺菌劑成為農(nóng)藥領(lǐng)域的研究熱點(diǎn)。

2,4-二氯苯基、1,2,4-三唑和喹唑啉作為活性藥效基團(tuán)[1-7]，在新農(nóng)藥創(chuàng)制中應(yīng)用廣泛。戊菌唑、糠菌唑、己唑醇、戊菌唑和啶斑肟等農(nóng)藥中含2,4-二氯苯基結(jié)構(gòu)；三唑酮、亞胺唑、唑蚜威等高效低毒的農(nóng)藥中含有1,2,4-三唑結(jié)構(gòu)；喹螨醚、氟喹唑等農(nóng)藥中含有喹唑啉基團(tuán)。

1,3,4-噻二嗪也是重要的藥效基團(tuán)，具有抗菌、調(diào)節(jié)植物生長(zhǎng)、殺蟲和抗病毒等藥理活性[8-11]。喹唑啉結(jié)構(gòu)具有良好的農(nóng)藥抑菌活性[12-14]。高元磊等[15]合成的喹唑啉化合物對(duì)小麥赤霉病菌和蘋果腐爛病菌的抑制率優(yōu)于對(duì)照藥劑噁霉靈。楊緒紅等[16]合成的喹唑啉化合物對(duì)煙草青枯病菌的抑制率優(yōu)于對(duì)照藥劑噻菌酮。

拼接高活性藥效基團(tuán)，常能得到高活性農(nóng)藥制劑。如烯唑醇、亞胺唑、唑啶草酮、氟醚唑，同時(shí)含有2,4-二氯苯基和1,2,4-三唑基團(tuán)；氟喹唑同時(shí)含有2,4-二氯苯基、1,2,4-三唑基團(tuán)和喹唑啉基團(tuán)。本文根據(jù)活性基團(tuán)拼接原理，將2,4-二氯苯基、1,2,4-三唑、1,3,4-噻二嗪結(jié)構(gòu)引入喹唑啉結(jié)構(gòu)中，設(shè)計(jì)并合成了13個(gè)未見文獻(xiàn)報(bào)道的含2,4-二氯苯基的1,2,4-三唑1,3,4-噻二嗪喹唑啉化合物(9a～9m， Scheme 1)，收率59%～74%，其結(jié)構(gòu)經(jīng)1H NMR,13C NMR,19F NMR和MS表征。采用濁度法測(cè)試目標(biāo)化合物對(duì)柑橘潰瘍病菌(Xac)、煙草青枯病菌(Rs)、水稻百葉枯病菌(Xoo)的抑制活性。

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

X-5型熔點(diǎn)儀;JEOL-ECX 400 MHz型核磁共振儀(DMSO-d6為溶劑，TMS為內(nèi)標(biāo));TSQ 8000/MSD三級(jí)四級(jí)桿氣相色譜質(zhì)譜。

化合物1～5[3], 2-(2-氯乙酰氨基)-3-甲基-N-甲基苯甲酰胺(8)[17]按文獻(xiàn)方法合成;2,4-二氯苯甲酸，2-氨基-3-甲基苯甲酸，上海阿拉丁試劑有限公司；其余所用試劑均為分析純。

1.2 9a～9m的合成通法

將中間體52 mmol和1%KOH溶液100 mL加入250 mL反應(yīng)瓶中，攪拌至澄清；緩慢滴加中間體80.51g(2.1mmol)的乙醇(40 mL)溶液，滴畢，攪拌下于50 ℃反應(yīng)至終點(diǎn)(TLC檢測(cè))。冰浴冷卻，抽濾，濾餅用冰乙醇洗滌，經(jīng)硅膠柱層析[洗脫劑：V(石油醚)/V(乙酸乙酯)=3/1]純化得9a～9m。

3-(2,4-二氯苯基)-6-(4-溴苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9a): 白色晶體, 產(chǎn)率62%, m.p.164～166 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.95(d,J=8.0 Hz, 1H, quinazoline-H), 7.86(s, 1H, 2,4-2ClPh-H), 7.64(s, 3H, 2,4-2ClPh-H+NH), 7.53(d,J=8.0 Hz, 2H, 4-BrPh-H), 7.41(t,J=8.0 Hz, 1H, quinazoline-H), 7.34(d,J=8.0 Hz, 2H, 4-BrPh-H), 7.25(d,J=4.0 Hz, 1H, quinazoline-H), 5.59(d,J=4.0 Hz, 1H, SCH), 5.26(t,J=4.0 Hz, 1H , NCH), 3.74(s, 3H, NCH3), 2.34(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 161.96, 153.93, 150.12, 144.92, 142.10, 136.78, 136.59, 135.58, 135.52, 134.96, 134.24, 131.98, 129.88, 129.76, 128.20, 127.40, 125.34, 124.36, 121.71, 120.50, 57.78, 30.55, 17.08; MSm/z: 615.0{[M+H]+}。

3-(2,4-二氯苯基)-6-苯基-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9b): 白色晶體, 產(chǎn)率59%, m.p.156～158 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 8.15(d,J=8.0 Hz, 1H, quinazoline-H), 7.62(d,J=4.0 Hz, 1H, 2,4-2ClPh-H), 7.56(d,J=1.6 Hz, 1H, Ph-H), 7.50(d,J=4.0 Hz, 1H, quinazoline-H), 7.43(t,J=8.0 Hz, 1H, quinazoline-H), 7.35(dd,J=4.0 Hz, 4.0 Hz, 1H, Ph-H), 7.27～7.29(m, 4H, Ph-H+NH), 7.26(s, 1H, ArH), 7.20(d,J=8.0 Hz, 1H, Ph-H), 5.44(d,J=4.0 Hz, 1H, SCH), 5.01(t,J=4.0 Hz, 1H, NCH), 3.75(s, 3H, NCH3), 2.60(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 161.94, 154.03, 150.14, 144.98, 142.35, 137.31, 136.54, 135.58, 135.20, 134.94, 134.18, 129.89, 129.08, 128.47, 128.17, 127.45, 127.08, 125.43, 124.36, 120.46, 58.67, 41.92, 30.53, 17.06; MSm/z: 536.1{[M+H]+}。

Scheme 1

3-(2,4-二氯苯基)-6-(3,4,5-三甲氧基苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9c): 白色晶體, 產(chǎn)率62%, m.p.196～198 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.93(d,J=8.0 Hz, 1H, quinazoline-H), 7.85(d,J=1.6 Hz, 1H, 2,4-2ClPh-H), 7.64(d,J=8.0 Hz, 1H, quinazoline-H), 7.63(d,J=1.6 Hz, 1H, 2,4-2ClPh-H), 7.66(s, 1H, 2,4-2ClPh-H), 7.42(t,J=8.0 Hz, 1H, quinazoline-H), 6.69(d,J=8.0 Hz, 2H, methoxyPh-H), 7.12(t,J=4.0 Hz, 1H, NH), 6.69(d,J=5.6 Hz, 1H, SCH), 5.10(d,J=4.0 Hz, 8.0 Hz, 1H, NCH), 3.80(s, 3H, OCH3), 3.74(s, 3H, CH3), 3.70(s, 6H, OCH3), 2.62(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 161.89, 153.75, 153.31, 150.21, 145.01, 142.81, 137.63, 136.53, 135.52, 135.21, 134.83, 134.10, 132.71, 129.94, 128.14, 127.38, 125.27, 124.37, 120.46, 105.22, 60.41, 59.92, 42.36, 30.68, 17.06; MSm/z: 626.2{[M+H]+}。

3-(2,4-二氯苯基)-6-(2-氟苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9d): 白色晶體, 產(chǎn)率68%, m.p.176～178 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.93(d,J=8.0 Hz, 1H, quinazoline-H), 7.82(s, 1H, 2,4-2ClPh-H), 7.62～7.64(m, 3H, 2,4-2ClPh-H+NH), 7.32～7.41(m, 2H, Ph-H), 7.20～7.25(m, 2H, Ph-H), 7.15(d,J=8.0 Hz, 1H, Ph-H), 7.09(d,J=8.0 Hz, 1H, Ph-H), 5.59(d,J=5.2 Hz , 1H, SCH), 5.40(t,J=4.0 Hz, 1H , NCH), 3.73(s, 3H, NCH3), 2.26(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 161.95, 161.04, 158.60, 153.28, 149.78, 145.02, 142.62, 136.58, 135.64, 135.17, 134.87, 134.15, 130.87, 130.78, 129.87, 128.46, 128.42, 128.18, 127.37, 125.34, 125.30, 125.27, 125.20, 124.31, 120.49, 116.32, 116.10, 56.51, 53.91, 42.54, 30.45, 30.43, 19.03, 16.74;19F NMR(DMSO-d6, 400 MHz)δ: -115.72, -117.07; MSm/z:554.2{[M+H]+}。

3-(2,4-二氯苯基)-6-(2-羥基-5-溴苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9e): 白色晶體, 產(chǎn)率64%, m.p.201～202 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 7.96(d,J=8.0 Hz, 1H, quinazoline-H), 7.86(d,J=8.0 Hz, 1H, 2,4-2ClPh-H), 7.68(d,J=8.0 Hz, 1H, quinazoline-H), 7.61(d,J=4.0 Hz, 1H, 2,4-2ClPh-H), 7.37～7.41(m, 5H, Ph-H), 6.82(d,J=8.0 Hz, 1H, NH), 6.00(d,J=8.0 Hz , 1H, SCH), 5.49(t,J=4.0 Hz, 8.0 Hz , 1H, NCH), 4.82(s, 1H, OH), 3.42(s, 3H, CH3), 2.39(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 167.52, 161.98, 161.61, 157.75, 157.25, 151.82, 150.97, 150.18, 149.06, 144.99, 144.52, 137.17, 136.73, 136.01, 135.53, 135.23, 133.84, 133.59, 133.18, 129.95, 129.50, 128.86, 128.59, 128.03, 127.85, 127.72, 127.60, 126.91, 124.40, 124.35, 120.85, 120.75, 120.26, 112.99, 112.73, 112.63, 87.15, 63.73, 60.23, 38.02, 30.60, 25.96, 19.03, 17.28, 17.18, 16.89, 14.55; MSm/z: 631.3{[M+H]+}。

Scheme 2

3-(2,4-二氯苯基)-6-(2-羥基-5-甲基苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9f): 白色晶體, 產(chǎn)率63%, m.p.186～188 ℃;1H NMR(DMSO-d6,400 MHz)δ: 14.11(s, 1H, OH), 7.96(d,J=8.0 Hz, 1H, quinazoline-H), 7.91(d,J=4.0 Hz, 1H, 2,4-2ClPh-H), 7.64(d,J=8.0 Hz, 1H, quinazoline-H), 7.58(dd,J=4.0 Hz, 4.0 Hz, 1H, Ph-H), 7.43(t,J=8.0 Hz, 1H, Ph-H), 7.31(d,J=8.0 Hz, 1H, Ph-H), 7.13(d,J=4.0 Hz, 1H, Ph-H), 7.00(d,J=8.0 Hz, 1H, Ph-H), 6.67(d,J=8.0 Hz, 1H, NH), 6.58(s, 1H, Ph-H), 6.15(t,J=4.0 Hz, 8.0 Hz, 1H, SCH), 5.90(d,J=4.0 Hz, 1H, SCH), 3.62(s, 3H, CH3), 2.34(s, 3H, CH3), 2.19(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 167.56, 162.05, 156.18, 151.34, 149.11, 144.59, 137.03, 136.01, 135.35, 135.21, 133.93, 130.91, 130.54, 129.94, 128.01, 127.64, 126.14, 125.92, 124.33, 124.23, 120.74, 110.04, 86.66, 63.57, 30.60, 20.85, 15.93; MSm/z: 565.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(2-羥基苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9g): 白色晶體, 產(chǎn)率65%, m.p.206～208 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 14.14(s, 1H, OH), 7.96(d,J=8.0 Hz, 1H, quinazoline-H), 7.86(d,J=4.0 Hz, 1H, 2,4-2ClPh-H), 7.63(d,J=8.0 Hz, 1H, quinazoline-H), 7.54(dd,J=4.0 Hz, 4.0 Hz, 1H, Ph-H), 7.44(t,J=8.0 Hz, 1H, ArH), 7.17～7.35(m, 4H, Ph-H), 6.99(s, 1H, Ph-H), 6.92(t,J=8.0 Hz, 1H, Ph-H), 6.80(d,J=8.0 Hz, 1H, ArH), 6.29(t,J=4.0 Hz, 1H, SCH), 5.83(s, 1H, SCH), 3.61(s, 3H, CH3), 2.33(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ: 167.52, 162.02, 158.43, 151.13, 149.11, 144.54, 136.99, 136.03, 135.30, 135.24, 135.20, 133.71, 130.63, 129.89, 127.89, 127.65, 125.87, 125.81, 124.33, 124.15, 121.81, 120.75, 110.53, 86.52, 63.11, 60.23, 30.56, 21.23, 16.87, 14.56; MSm/z: 551.1{[M]+}。

3-(2,4-二氯苯基)-6-(4-甲氧基苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9h): 白色晶體, 產(chǎn)率56%, m.p.216～218 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.94(d,J=8.0 Hz, 1H, quinazoline-H), 7.86(s, 1H, 2,4-2ClPh-H), 7.63～7.71(m, 3H, Ph-H+NH), 7.43(t,J=8.0 Hz, 1H, quinazoline-H), 7.29(d,J=8.0 Hz, 2H, 4-OCH3Ph-H), 7.12～7.17(m, 1H, Ph-H), 6.85(d,J=8.0 Hz, 2H, 4-OCH3Ph-H), 5.55(d,J=4.0 Hz, 1H, SCH), 5.14(t,J=4.0 Hz, 1H, NCH), 3.59～3.83(m, 6H, CH3+OCH3), 2.38(s, 3H, CH3);13C NMR(125 MHz, DMSO-d6)δ:161.91, 159.56, 159.28, 154.07, 150.24, 145.00, 142.43, 136.52, 135.58, 135.22, 134.95, 134.20, 129.88, 129.03, 128.77, 128.38, 128.17, 127.94, 127.37, 125.45, 124.37, 120.44, 115.26, 114.42, 60.56, 58.52, 55.53, 42.03, 30.55, 17.11; MSm/z: 566.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(2,4-二氟苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9i): 白色晶體, 產(chǎn)率66%, m.p.191～193 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.93(d,J=8.0 Hz, 1H, quinazoline-H), 7.84(d,J=8.0 Hz, 1H, 2,4-2ClPh-H),7.62～7.64(m, 3H, Ph-H+NH), 7.40(t,J=8.0 Hz, 1H, quinazoline-H), 7.27～7.34(m, 2H, Ph-H), 7.04～7.12(m, 2H, Ph-H), 5.57(d,J=4.0 Hz , 1H, SCH), 5.36(t,J=4.0 Hz、8.0 Hz, 1H, NCH), 3.71(s, 2H, CH3), 2.27(s, 2H, CH3);19F NMR(DMSO-d6, 400 MHz)δ: -111.02, -109.02, -109.63, -111.18, -112.56, -113.02;13C NMR(125 MHz, DMSO-d6)δ: 161.72, 158.26, 153.19, 152.03, 149.82, 149.02, 147.04, 145.09, 144.99, 142.53, 136.91, 136.60, 135.34, 135.21, 135.06, 134.26, 134.19, 134.16, 130.09, 129.87, 128.30, 128.19, 126.93, 125.23, 124.36, 120.50, 120.24, 105.64, 30.51, 30.46, 17.05, 16.77; MSm/z: 571.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(2,4,6-三氟苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9j): 白色晶體, 產(chǎn)率64%, m.p.182～184 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 7.93(d,J=8.0 Hz, 1H, quinazoline-H), 7.84(d,J=8.0 Hz, 1H, 2,4-2ClPh-H), 7.62～7.64(m, 3H, Ph-H +NH), 7.41(t,J=8.0 Hz, 1H, quinazoline-H), 7.27～7.34(m, 1H, Ph-H), 7.04～7.12(m, 2H, Ph-H), 5.61(t,J=8.0 Hz, 1H, NCH), 5.55(d,J=4.0 Hz, 1H, SCH), 3.64(s, 3H, CH3), 2.33(s, 3H, CH3);19F NMR(DMSO-d6,400 MHz)δ: -106.50, -108.78;13C NMR(125 MHz, DMSO-d6)δ: 161.75, 152.31, 150.25, 144.77, 143.32, 136.60, 135.66, 135.40, 134.73, 134.18, 129.95, 128.78, 127.70, 125.05, 124.43, 120.47, 102.16, 101.87, 54.59, 43.46, 30.62, 16.74; MSm/z: 589.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(4-氟苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9k): 白色晶體, 產(chǎn)率62%, m.p.189～191 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 7.95(d,J=8.0 Hz, 1H, quinazoline-H), 7.86(s, 1H, 2,4-2ClPh-H), 7.63-7.67(m, 3H, Ph-H), 7.40～7.45(m, 3H, Ph-H), 7.22(d,J=8.0 Hz, 1H, quinazoline-H), 7.17(t,J=8.0 Hz, 1H, quinazoline-H), 5.58(d,J=8.0 Hz, 1H, SCH), 5.24( t,J=8.0 Hz, 4.0 Hz, 1H, NCH), 3.72(s, 3H, CH3), 2.35(s, 3H, CH3);19F NMR(DMSO-d6,400 MHz)δ: -114.06;13C NMR(125 MHz, DMSO-d6)δ: 163.29, 161.94, 160.85, 153.98, 150.16, 144.94, 142.23, 136.57, 135.58, 135.22, 134.96, 134.22, 133.56, 133.53, 129.89, 129.73, 129.66, 128.18, 127.39, 125.37, 124.37, 120.47, 116.02, 115.80, 57.99, 55.39, 41.75, 30.56, 17.10; MSm/z: 553.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(2-氯-4-氟苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9l): 白色晶體, 產(chǎn)率61%, m.p.187～189 ℃;1H NMR(DMSO-d6, 400 MHz)δ: 7.91(d,J=8.0 Hz, 1H, quinazoline-H), 7.83(s, 1H, 2,4-2ClPh-H), 7.56～7.63(m, 4H, Ph-H+NH), 7.45(dd,J=4.0 Hz, 4.0 Hz, 1H, Ph-H), 7.40(t,J=4.0 Hz, 1H, Ph-H), 7.16～7.23(m, 2H, Ph-H), 5.74(d,J=8.0 Hz, 1H, SCH), 5.48(t,J=8.0 Hz, 1H, NCH), 3.72(s, 3H, CH3), 2.34(s, 3H, CH3);19F NMR(DMSO-d6, 400 MHz)δ: -110.23, -110.88；13C NMR(125 MHz, DMSO-d6)δ: 163.11, 161.73, 161.36, 160.63, 153.07, 153.00, 150.36, 149.21, 145.02, 144.88, 143.02, 142.68, 136.55, 136.14, 136.07, 135.56, 135.31, 135.14, 134.92, 134.87, 134.76, 134.53, 134.22, 131.60, 130.17, 130.08, 129.85, 128.05, 127.88, 127.56, 127.39, 125.32, 125.09, 124.38, 120.33, 119.89, 117.84, 117.59, 115.34, 115.13, 58.20, 57.81, 42.50, 31.00, 30.00, 17.12, 16.79; MSm/z: 587.1{[M+H]+}。

3-(2,4-二氯苯基)-6-(2,5-二氯苯基)-7-[3,8-二甲基喹唑啉-4(3H)-酮]-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪(9m): 白色晶體, 產(chǎn)率61%, m.p.182～184 ℃;1H NMR(DMSO-d6,400 MHz)δ: 7.91(d,J=8.0 Hz, 1H, quinazoline-H), 7.83(d,J=2.0 Hz, 1H, Ph-H), 7.56～7.63(m, 4H, Ph-H), 7.50(d,J=8.0 Hz, 1H, Ph-H), 7.42(d,J=4.0 Hz, 1H, Ph-H), 7.40(s, 1H, Ph-H), 7.21(d,J=8.0 Hz, 1H, Ph-H), 5.68(d,J=8.0 Hz, 1H, SCH), 5.48(t,J=8.0 Hz, 1H, SCH), 3.72(s, 3H, CH3), 2.34(s, 3H, CH3).13C NMR(125 MHz, DMSO-d6)δ: 161.83, 153.38, 150.25, 144.85, 143.31, 137.14, 136.62, 135.57, 135.33, 134.86, 134.16, 132.58, 132.23, 131.99, 130.46, 129.92, 128.63, 128.10, 127.58, 125.02, 124.39, 120.35, 58.24, 42.61, 31.10, 17.13; MSm/z: 605.1{[M+H]+}。

1.3 抑菌活性測(cè)試

供試藥劑濃度為100 μg/mL和50 μg/mL。采用濁度法測(cè)試目標(biāo)化合物對(duì)柑橘潰瘍病菌、煙草青枯病菌、水稻百葉枯病菌的抑制活性[13]。

2 結(jié)果與討論

2.1 反應(yīng)機(jī)理

TLC跟蹤結(jié)果顯示，中間體1生成后,隨即就有中間體3出現(xiàn),最終全部轉(zhuǎn)化為6。由此，分析可能的反應(yīng)機(jī)理見Scheme 2：首先生成了硫醚,由于C=O的強(qiáng)吸電子作用,使CH2變得活潑,在KOH堿性下，CH2生成碳負(fù)離子，作為親核試劑與C=N雙鍵發(fā)生分子內(nèi)親核加成反應(yīng)得中間體3；在堿性條件下，受1,2,4-三唑[3,4-b][1,3,4]噻二嗪環(huán)的吸電子誘導(dǎo)效應(yīng)影響，酰胺鍵烯醇化，然后發(fā)生分子內(nèi)閉環(huán)脫去H2O后生成喹唑啉酮。

2.2 表征

以化合物9c(Chart 1)的為例，分析了1H NMR數(shù)據(jù)。δ7.93處特征峰為1-H的吸收峰，受2-H耦合作用影響，裂分為雙重峰。δ7.64處特征峰為3-H的吸收峰，受2-H耦合作用影響，裂分為雙重峰。δ7.42處特征峰為2-H的吸收峰，1-H和3-H耦合作用影響，裂分為三重峰。δ7.85處特征峰為8-H的吸收峰，受9-H耦合作用影響，裂分為兩重峰。δ7.63處特征峰為9-H的吸收峰，受8-H耦合作用影響，裂分為雙重峰。δ7.66處特征峰為10-H的吸收峰，為單峰。δ6.69處特征峰為4-H和5-H的吸收峰，化學(xué)環(huán)境相同，為單峰。δ 7.12處特征峰為N—H的吸收峰，受6-H耦合作用影響，裂分為兩重峰。δ6.69處特征吸收峰為S—C—H吸收峰，受6-H耦合作用的影響，裂分為兩重峰。δ5.10處特征吸收峰為6-H吸收峰，受7-H耦合作用的影響，裂分為三重峰。

表1 9a～9m對(duì)植物病菌的抑制率*

*A: 100 μg/mL, B: 50μg/mL。

Chart 1

2.2 抑菌活性

表1為目標(biāo)化合物對(duì)水稻白葉枯病菌(Xoo)、柑橘潰瘍病菌(Xac)和煙草青枯病菌(Rs)的抑制活性。從表1可以看出，目標(biāo)化合物對(duì)植物病菌的抑制作用與取代基性質(zhì)有關(guān)?；衔?d、9i、9j、9k、9l的結(jié)構(gòu)中含有氟原子，活性相對(duì)較高，可能是氟原子的電子效應(yīng)，使目標(biāo)化合物分子的電荷分布產(chǎn)生變化，提高了電子云密度，進(jìn)而增強(qiáng)了此類化合物在細(xì)菌體中的吸收、傳遞速度和穿透力。當(dāng)R為羥基取代時(shí)，化合物活性相對(duì)較好，原因可能是羥基的引入提高了化合物的溶解性，使目標(biāo)化合物更容易與受體結(jié)合。當(dāng)濃度為100 μg/mL時(shí),化合物9d、9i、9j對(duì)柑橘潰瘍病菌的抑制率分別為63.5%、 65.2%、 58.3%，與對(duì)照藥劑噻菌酮(57.2%)和葉枯唑(65.3%)相當(dāng)。當(dāng)濃度為50 μg/mL時(shí),化合物9j對(duì)柑橘潰瘍病菌的抑制率為56.4 %，與對(duì)照藥劑葉枯唑(54.9%)相當(dāng)。當(dāng)濃度為100 μg/mL時(shí),化合物9i、9j對(duì)水稻百葉枯病菌的抑制率分別為65.3%和62.3%，和對(duì)照藥劑噻菌酮(50.2%)、葉枯唑(64.9%)相當(dāng)。當(dāng)濃度為50 μg/mL時(shí)，化合物9j對(duì)水稻百葉枯病菌的抑制率為48.5%，和對(duì)照藥劑噻菌酮(37.2%)和葉枯唑(45.2%)相當(dāng)。

合成了13個(gè)新型的含2,4-二氯苯基的1,2,4-三唑1,3,4-噻二嗪喹唑啉酮化合物(9a～9m)，并采用濁度法測(cè)試了生物活性。結(jié)果表明，化合物9k和9j對(duì)柑橘潰瘍病菌和水稻百葉枯病菌的抑制率和對(duì)照藥劑相當(dāng)，具備進(jìn)一步開發(fā)的價(jià)值。