陳佰靈,趙志剛,劉興利,石治川,鄭禮婷(西南民族大學(xué)化學(xué)與環(huán)境保護(hù)工程學(xué)院,四川 成都 610041)
新型吲哚席夫堿類(lèi)化合物的合成及其抗菌活性研究
陳佰靈,趙志剛,劉興利,石治川,鄭禮婷
(西南民族大學(xué)化學(xué)與環(huán)境保護(hù)工程學(xué)院,四川 成都 610041)
摘 要:以吲哚-3-甲酸甲酯為原料,通過(guò)偶聯(lián)、肼解、消除等反應(yīng),合成了一系列具有對(duì)稱結(jié)構(gòu)的吲哚席夫堿衍生物,以期為新藥篩選提供先導(dǎo)化合物.其結(jié)構(gòu)均經(jīng)1H NMR,ESI-MS,IR及元素分析所證實(shí).初步抗菌活性測(cè)定結(jié)果表明:化合物5e對(duì)枯草芽孢桿菌、金黃色葡萄球菌具有較強(qiáng)的抑菌效果;化合物5f對(duì)大腸桿菌的抑菌效果優(yōu)于阿莫西林,對(duì)綠膿桿菌表現(xiàn)出與對(duì)照品阿莫西林相當(dāng)?shù)囊志Ч?
關(guān)鍵詞:吲哚;席夫堿;抗菌活性
雜環(huán)化合物是眾所周知藥效廣泛的醫(yī)藥中間體,其獨(dú)特結(jié)構(gòu)為藥物發(fā)展提供了新的方向[1].吲哚及其衍生物是重要的稠環(huán)雜環(huán)化合物,因其獨(dú)特的結(jié)構(gòu)和潛在的藥物生理活性、相對(duì)較低的毒性、高效的生物相容性,在雜環(huán)化學(xué)中占有重要的地位[2].吲哚衍生物在醫(yī)藥方面可以合成解熱鎮(zhèn)痛劑、血管擴(kuò)張藥、抗組胺藥、抗腫瘤藥等[3-4];在農(nóng)藥方面,可作為高效植物生長(zhǎng)調(diào)節(jié)劑、殺菌劑等[5-8].近年來(lái),醫(yī)藥和農(nóng)藥的合成正趨向于選擇雜環(huán)化合物以適應(yīng)生物進(jìn)化對(duì)新型農(nóng)藥和醫(yī)藥的需求.故而在雜環(huán)化學(xué)中占有重要地位的吲哚類(lèi)化合物具有值得進(jìn)一步深入研究和開(kāi)發(fā)的價(jià)值.席夫堿的基本結(jié)構(gòu)中含有亞胺(-N = CH-)基團(tuán),可通過(guò)伯氨與活潑羰基縮合反應(yīng)得到.由于其特殊的生理活性和良好的配位能力,在醫(yī)藥領(lǐng)域越來(lái)越有重要的應(yīng)用如抗腫瘤、抗病毒、抗細(xì)菌、抗真菌、抗瘧疾、抗細(xì)胞增殖等[9-13],具有潛在的藥用價(jià)值.
將具有不同生物活性的官能團(tuán)在同一分子中聚集,實(shí)現(xiàn)活性的疊加,是開(kāi)發(fā)新的具有高效,廣譜活性的新化合物的有效方法.本課題組已經(jīng)合成了一系列根據(jù)活性疊加原理設(shè)計(jì)的高效廣譜活性的新化合物[14-16].因此本文以吲哚-3-甲酸甲酯為原料,通過(guò)偶聯(lián)、肼解、消除等反應(yīng),合成了具有對(duì)稱結(jié)構(gòu)的雙席夫堿吲哚化合物(5a-5l,Scheme 1).并測(cè)試了這些化合物對(duì)四種致病菌株(枯草芽孢桿菌、金黃色葡萄球菌、大腸桿菌、綠膿桿菌)的抑菌活性.
路線圖1 目標(biāo)化合物5a-5l合成Scheme 1 Synthesis protocol of 5a-5l
1.1 儀器與試劑
Agilent-NMR-vnmrs400MHz型核磁共振儀(TMS作內(nèi)標(biāo),DMSO-d6作溶劑);WRS-1B型數(shù)字顯示顯微熔點(diǎn)儀(溫度未校正);FINNIGAN-LCQ ADVANTAGE MAX型質(zhì)譜儀;PERKIN-ELMER1700型紅外光譜儀(KBr壓片); VarioMICRO自動(dòng)元素分析儀;銳品ECA-9272型電熱恒溫培養(yǎng)箱;東聯(lián)DL-CJ-1N型垂直層流潔凈工作臺(tái);三申YX280A型手提式高壓蒸汽滅菌鍋;友聯(lián)HY-2A型數(shù)顯調(diào)速多用振蕩器.供試菌種枯草芽孢桿菌(ATCC 6633)、金黃色葡萄球菌(ATCC 6538)、大腸桿菌(ATCC 35218)及綠膿桿菌(ATCC 27853);其余所用試劑均為分析純.
1.2 合成
(1)中間體3的合成
在反應(yīng)管中加入1.75 g(10 mmol)吲哚-3-甲酸甲酯1,0.4 mL(0.45 mmol)1,2-二溴乙烷2,0.94g(6.8 mmol)K2CO3和10 mL無(wú)水DMF,在室溫下攪拌反應(yīng)24 h(TLC監(jiān)測(cè)),反應(yīng)完全后,通過(guò)柱層析得到中間體3.白色固體,產(chǎn)率65%,m.p.179-180°C;1H NMR (400 MHz,CDCl3)δ:8.19-8.17(m,2H,ArH),7.38 (s,2H,Indole-CH),7.31-7.23(m,6H,ArH),4.54(s,4H,CH2CH2),3.85(s,6H,COOCH3);IR(KBr):2945,1694,1380,1177,1080,750 cm-1;ESI-MS m/ z(%): 399([M+Na]+,100).Ana1.Calcd for C22H20N2O4: C,70.20; H,5.36; N,7.44% .Found: C,70.21; H,5.38;N,7.47%.
(2)中間體4的合成
在反應(yīng)瓶中將0.376 g(1 mmol)中間體3溶于5mL水合肼(80%)中,在60°C反應(yīng)20 h(TLC監(jiān)測(cè)反應(yīng)進(jìn)程),反應(yīng)結(jié)束后冷卻,過(guò)濾,用無(wú)水乙醇重結(jié)晶得到中間體4.白色固體,產(chǎn)率97%,m.p.249-250° C;1H NMR (400 MHz,CDCl3)δ: 11.35 ( s,2H,CONH),8.27-8.20 (m,4H,Indole-H),8.17 (s,2H,CONH),7.38(s,2H,Indole-CH),7.30-7.21(m,6H,ArH),4.53(s,4H,CH2CH2),1.60(s,4H,NH2);IR (KBr):3347,1690,1623,750 cm-1;ESI-MS m/ z(%): 377([M+H]+,100).Ana1.Calcd for C20H20N6O2:C,63.82;H,5.36;N,22.33%.Found:C,63.80;H,5.37; N,22.31%.
(3)目標(biāo)化合物5的合成通法
在反應(yīng)瓶中加入0.376 g(1 mmol)中間體4,2mmol芳香醛,5 mL無(wú)水DMF,用冰醋酸調(diào)節(jié)pH值至4左右,于90°C下攪拌反應(yīng)8 h(TLC監(jiān)測(cè)反應(yīng)進(jìn)程),反應(yīng)完全后冷卻有固體析出,過(guò)濾,用乙醇重結(jié)晶得5a-5l.
5a:棕色固體,產(chǎn)率85%,m.p.249-250°C;1H NMR(400 MHz,DMSO-d6)δ:11.35(s,2H,CONH),8.27-8.20(m,4H,Indole-H),8.17(s,2H,ArCH = N),7.87(d,2H,J = 7.2 Hz,ArH),7.58(d,J = 8.0 Hz,2H,Indole-H),7.30-7.23(m,4H,Indole-H),6.89(d,2H,J =7.6 Hz,ArH),6.69(d,2H,J =7.2 Hz,ArH),4.81(s,4H,CH2CH2);IR(KBr):3206,1635,1606,1533,834cm-1;ESI-MS m/ z(%):532.9([M+H]+,100).Ana1.Calcd for C30H24N6O4:C,67.66;H,4.54; N,15.78%.Found:C,66.77;H,4.52;N,15.75%.
5b:淡黃色固體,產(chǎn)率76%,m.p.300-301°C;1H NMR(400 MHz,DMSO-d6)δ:11.17(s,2H,CONH),8.20-8.11(m,4H,Indole-H),8.09(s,2H,ArCH = N),7.62-7.56(m,2H,Indole-H),7.49(d,4H,J =8.8 Hz,ArH),7.22-7.15(m,4H,Indole-H),6.98(d,2H,J = 8.4 Hz,ArH),4.75(s,4H,CH2CH2),3.79(s,6H,Ar-OCH3);IR (KBr):3442,1638,1606,1513,834cm-1; ESI-MS m/ z(%):1247.1([2M+Na]+,100).Ana1.Calcd for C36H32N6O4:C,70.57;H,5.26;N,13.72%.Found:C,70.55;H,5.29;N,13.69%.
5c:棕色固體,產(chǎn)率79%,m.p.286-287°C;1H NMR(400 MHz,DMSO-d6)δ:11.42(s,2H,CONH),8.46-7.95(m,8H,ArH and ArCH = N),7.48(brs,4H,ArH),7.19(brs,6H,ArH and Indole-H),6.91(d,2H,J = 7.2 Hz,Indole-H),4.75 ( s,4H,CH2CH2); IR (KBr):3161,1640,1605,1526,1182,782,747cm-1; ESI-MS m/ z (%):588.9 ([ M+H]+,100).Ana1.Calcd for C34H26F2N6O4: C,69.38; H,4.45; N,14.28%.Found:C,69.40;H,4.43;N,14.30%.
5d:淡黃色固體,產(chǎn)率65%,m.p.274-275℃;1H NMR(400 MHz,DMSO-d6)δ:11.85 ( s,2H,OH),11.62(s,2H,CONH),8.46(s,2H,ArCH = N),8.20-8.18(m,2H,Indole-H),8.05(s,2H,Indole-H),7.97-7.94(m,2H,ArH and Indole-H),7.50-7.43(m,4H,ArH),7.21-7.14 (m,4H,ArH and Indole-H),6.93-6.88 ( m,4H,ArH and Indole-H ),4.72 ( s,4H,CH2CH2);IR ( KBr):3432,3016,1636,1602,1530,1165,746cm-1; ESI-MS m/ z (%): 1190.9 ([ 2M+Na]+,100).Ana1.Calcd for C34H28N6O4:C,69.85;H,4.83; N,14.38% .Found: C,69.88; H,4.80; N,14.33%.
5e:棕色固體,產(chǎn)率78%,m.p.332-333°C;1H NMR(400 MHz,DMSO-d6)δ:11.35(s,2H,CONH),8.20(s,2H,ArCH = N),8.04-7.95(m,4H,Indole-H),7.63-7.47(m,10H,ArH and Indole-H),7.19(d,2H,J =6.8 Hz,ArH),4.75(s,4H,CH2CH2);IR(KBr): 3161,1636,1600,1521,1089,841.ESI-MS m/ z(%): 642.9([ M+Na+]+,100) .Ana1.Calcd for C34H26Cl2N6O2: C,65.71; H,4.22; N,13.52% .Found: C,65.66;H,4.26;N,13.50%.
5f:白色固體,產(chǎn)率80%,m.p.340-341°C;1H NMR(400 MHz,DMSO-d6)δ:11.29(s,2H,CONH),8.20(s,2H,ArCH = N),8.04 (d,4H,J = 6.4 Hz,ArH),7.82-7.68(m,2H,Indole-H),7.49(d,4H,J = 6.8 Hz,ArH),7.24-7.11(m,8H,Indole-H),4.76(s,4H,CH2CH2); IR ( KBr): 3159,1644,1605,1550,1165,841.ESI-MS m/ z (%):588.9 ([ M+Na+]+,100).Ana1.Calcd for C34H26F2N6O2: C,69.38; H,4.45; N,14.28% .Found: C,69.33; H,4.44; N,14.30%.
5g:黃色固體,產(chǎn)率73%,m.p.265-266°C;1HNMR(400 MHz,DMSO-d6)δ:11.62(s,2H,CONH),8.39-8.21(m,8H,ArH and Indole-H),8.11(s,2H,ArCH = N),7.96-7.82(m,4H,Indole-H),7.61-7.56 (m,2H,Indole-H),7.38-7.21(m,4H,ArH),4.86(s,4H,CH2CH2); IR ( KBr): 3436,1638,1605,1552,1515,1338,840.ESI-MS m/ z (%):1307.1 ([2M+Na+]+,100).Ana1.Calcd for C34H26N8O6:C,63.55; H,4.08; N,17.44% .Found: C,63.53; H,4.10; N,17.44%.
5h:白色固體,產(chǎn)率60%,m.p.283-284°C;1H NMR(400 MHz,DMSO-d6)δ:11.56(s,2H,CONH),8.88(s,2H,ArCH = N),8.63-8.59(m,4H,Indole-H),8.21-8.19(m,2H,ArH),7.50-7.48(m,4H,ArH and Indole-H),7.42-7.40 ( m,4H,ArH and Indole-H),7.20-7.16(m,4H,ArH and Indole-H),4.75(s,4H,CH2CH2);IR ( KBr):3170,1634,1607,1526,1049,746.ESI-MS m/ z (%):643.1 ([M+Na+]+,100).Ana1.Calcd for C34H26Cl2N6O2:C,65.71;H,4.22;N,13.52%.Found:C,65.68;H,4.25;N,13.50%.
5i:白色固體,產(chǎn)率82%,m.p.285-286°C;1H NMR(400 MHz,DMSO-d6)δ:11.57(s,2H,CONH),8.58(s,2H,ArCH = N),8.20-7.91(m,4H,ArH and Indole-H),7.66(d,2H,J = 6.4 Hz,ArH),7.49-7.33 (m,8H,ArH and Indole-H),7.19-7.17(m,4H,ArH and Indole-H),4.75 ( s,4H,CH2CH2); IR ( KBr): 3178,1635,1604,1526,1056,750.ESI-MS m/ z(%): 1442.7([2M+Na+]+,100).Ana1.Calcd for C34H26Br2N6O2:C,57.48; H,3.69; N,11.83% .Found: C,57.44;H,3.72;N,11.85%.
5j:淡黃色固體,產(chǎn)率80%,m.p.311-312°C;1H NMR(400 MHz,DMSO-d6)δ:11.36(s,2H,CONH),8.20(s,2H,ArCH = N),8.05-7.92(m,4H,Indole-H),7.62-7.49 ( m,10H,ArH and Indole-H),7.20-7.17 (m,4H,ArH),4.75 ( s,4H,CH2CH2); IR ( KBr): 3154,1640,1601,1555,1110,839.ESI-MS m/ z(%): 733.0([ M+Na+]+,100) .Ana1.Calcd for C34H26Br2N6O2:C,57.48; H,3.69; N,11.83% .Found: C,57.50;H,3.70;N,11.85%.
5k:黑色固體,產(chǎn)率65%,m.p.310-311°C;1H NMR(400 MHz,DMSO-d6)δ:10.98(s,2H,CONH), 8.18(s,2H,ArCH = N),8.00-7.48(m,5H,Indole-H),7.23-7.04(m,5H,Indole-H),4.73(s,4H,CH2CH2),4.73(s,4H,H-2 H-5,F(xiàn)c),4.31(s,4H,H-3 H-4,F(xiàn)c),4.20(s,10H,F(xiàn)c-unsubst ring);IR(KBr):3406,1602,1601,1540,1100,1008.ESI-MS m/ z(%):769.9([M +H+]+,100) .Ana1.Calcd for C42H36Fe2N6O2:C,65.64;H,4.72;N,10.94%.Found:C,65.66;H,4.75; N,10.90%.
5l:棕色固體,產(chǎn)率74%,m.p.259-260°C;1H NMR(400 MHz,DMSO-d6)δ:13.75 ( s,2H,NH),12.81(s,2H,CONH),8.29(s,2H,ArCH = N),7.98-7.95( m,4H,Indole-H),7.68 ( d,2H,J = 9.6 Hz,ArH),7.49(d,2H,J = 8.8 Hz,ArH),7.35(s,2H,indole-H),7.18(d,4H,J = 2.4 Hz,Indole-H),4.77(s,4H,CH2CH2);IR(KBr):3046,1657,1612,1565.ESIMS m/ z(%):555.1([M+Na+]+,100).Ana1.Calcd for C28H24N10O2: C,63.15; H,4.54; N,26.30%.Found:C,63.20;H,4.55;N,26.33%.
1.3 抗菌活性測(cè)試
化合物5a-5l的體外抗菌活性測(cè)試使用革蘭氏陽(yáng)性菌(枯草芽孢桿菌、金黃色葡萄球菌)與革蘭氏陰性菌(大腸桿菌、綠膿桿菌),以阿莫西林作為陽(yáng)性對(duì)照,DMSO為陰性對(duì)照.采用二倍稀釋法與紙片擴(kuò)散法進(jìn)行抗菌活性篩選,每個(gè)測(cè)試重復(fù)三次.同時(shí)分別計(jì)算IC50與MIC值.
1.3.1 IC50值
用2 mL容量瓶,對(duì)目標(biāo)物和阿莫西林與環(huán)丙沙星分別選取無(wú)菌DMSO溶解定容,得到濃度為640μg/ mL的母液.取無(wú)菌試管將母液依次稀釋為640,320,160,80,40,20,10,5 μg/ mL,0 μg/ mL作為空白對(duì)照.將活化后的細(xì)菌接種在培養(yǎng)基中,菌液濃度配成0.5麥?zhǔn)媳葷針?biāo)準(zhǔn),約含1-2×108CFU/ mL,用MH肉湯將菌液進(jìn)行1:100稀釋后,用無(wú)菌棉沾取菌液在營(yíng)養(yǎng)瓊脂培養(yǎng)基平板表面均勻涂抹3次,室溫干燥10 min,將含有400 μL各梯度濃度藥液的無(wú)菌干燥濾紙片(直徑6 mm),貼放于培養(yǎng)基平板表面.37℃恒溫孵化18 h后得到抑菌圈直徑,測(cè)量并計(jì)算IC50值.
1.3.2 MIC值
將活化后的細(xì)菌接種在培養(yǎng)基中,菌液濃度配成0.5麥?zhǔn)媳葷針?biāo)準(zhǔn),用MH肉湯將菌液進(jìn)行1:100稀釋后備用.用2 mL容量瓶,對(duì)目標(biāo)物和阿莫西林分別選取無(wú)菌DMSO溶解定容,得到的母液濃度為:1280 μg/ mL.采用二倍稀釋法將依次稀釋至濃度為256,128,64,32,16,8,4,2,1,0.5,0.25 μg/ mL,0 μg/ mL作為空白對(duì)照.將1 mL配制好菌液加入各梯度濃度藥物原液,37°C恒溫孵化18 h后,觀察結(jié)果并記錄MIC值.
2.1 抗菌活性
表1為化合物5a-5l的抗菌活性數(shù)據(jù).部分測(cè)試的化合物對(duì)枯草芽孢桿菌、金黃色葡萄球菌、大腸桿菌和綠膿桿菌具有不同程度的抗菌活性.其中,對(duì)于枯草芽孢桿菌,5e最佳,其抑菌效果超過(guò)對(duì)照品阿莫西林;對(duì)于金黃色葡萄球菌,化合物5c,5e和5f都顯示出抑制效果,5e的效果優(yōu)于5c與5f;對(duì)于大腸桿菌,化合物5c、5e和5f都顯示出抑制效果,其中5f明顯優(yōu)于其他化合物和對(duì)照品阿莫西林;對(duì)于綠膿桿菌,化合物5a、5c和5f都顯示出抑菌效果,其中5f抑菌效果與標(biāo)準(zhǔn)對(duì)照藥物阿莫西林相當(dāng).該系列化合物其他方面的活性效果及化合物結(jié)構(gòu)與生物活性之間的關(guān)系正在進(jìn)一步研究中.
表1 目標(biāo)化合物5a~5l的抗菌活性Table 1 Antibacterial activities of target compounds 5a~5l
以吲哚-3-甲酸甲酯為起始原料,經(jīng)過(guò)偶聯(lián)、肼解、消除等反應(yīng),快速合成了一種結(jié)構(gòu)新穎的吲哚席夫堿類(lèi)衍生物,產(chǎn)率在60%~85%之間.抗菌活性測(cè)試結(jié)果表明:部分目標(biāo)化合物具有良好的抗菌活性,其中氟取代化合物顯示出比其它取代基更優(yōu)良的生物活性,化合物5e和5f的抗菌效果甚至優(yōu)于對(duì)照片阿莫西林的抗菌活性,這對(duì)新藥的研發(fā)提供了進(jìn)一步的研究依據(jù).
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(責(zé)任編輯:李建忠,付強(qiáng),張陽(yáng),羅敏;英文編輯:周序林,鄭玉才)
Synthesis and antibacterial activities of novel indole Schiff base derivatives
CHEN Bai-ling,ZHAO Zhi-gang,LIU Xing-li,SHI Zhi-chuan,ZHENG Li-ting
(School of Chemistry and Environmental Protection Engineering,Southwest University for Nationalities,Chengdu 610041,P.R.C.)
Abstract:A series of novel indole Schiff base derivatives were synthesized through coupling,hydrazine,and elimination reaction by using methyl indole-3-carboxylate as starting material.Their structures were elucidated by1H NMR,ESI-MS spectra,IR and elemental analyses.The antibacterial activities of compounds were tested against two kinds of bacteria.The preliminary results indicated that compound 5e had potent inhibition activity against B.subtilis and S.aureus;Compound 5f showed higher antibacterial activity against E.coli and similar effect against P.aeruginosa than the standard reference drug(amoxicillin),respectively.Key words:indole;Schiff base;antibacterial activity
中圖分類(lèi)號(hào):O621.3;R9
文獻(xiàn)標(biāo)志碼:A
文章編號(hào):2095-4271(2016)02-0170-06
doi:10.11920/ xnmdzk.2016.02.008
收稿日期:2015-12-23
通信作者:劉興利(1966 - ),女,漢族,四川都江堰人,教授,研究方向:藥物合成.E-mail:liuxingli2000@ swun.cn.
基金項(xiàng)目:四川省應(yīng)用基礎(chǔ)研究項(xiàng)目(2012JY0028);西南民族大學(xué)研究生創(chuàng)新型科研項(xiàng)目(CX2014SZ44)