CN118005545A - 小分子抗菌肽模拟物及其应用 - Google Patents
小分子抗菌肽模拟物及其应用 Download PDFInfo
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- CN118005545A CN118005545A CN202410013060.0A CN202410013060A CN118005545A CN 118005545 A CN118005545 A CN 118005545A CN 202410013060 A CN202410013060 A CN 202410013060A CN 118005545 A CN118005545 A CN 118005545A
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Abstract
本发明公开了小分子抗菌肽模拟物及其应用，小分子抗菌肽模拟物基于半胱氨酸骨架结构，通过在氨基端、羧基端、或侧链巯基基团进行化学修饰得到，其通式为本发明的小分子抗菌肽模拟物，可以引起细胞膜去极化、破坏细胞膜完整性，能快速杀菌，可抑制生物膜形成，具有一定的生物膜清除活性，且不易诱导细菌耐药性，具有良好的抗革兰氏阳性菌的活性，对MRSA和VRE等耐药菌表现出了良好的抗菌活性，可以解决当下抗耐药菌药物缺乏的问题，具有替代或辅助当前临床用抗生素治疗各种耐药菌引起的感染性疾病，可用于敏感菌及耐药菌引起的感染性疾病的治疗，具有高效抗菌活性、低毒性、不受传统耐药机制影响。
Description
技术领域
本发明属于医药领域，具体涉及一种小分子抗菌肽模拟物及其在感染性疾病治疗中的应用。
背景技术
抗生素是当前用于治疗细菌感染引起的疾病的主要药物。然而，随着抗生素在医药、畜牧养殖业和食品工业的广泛使用和滥用，出现了越来越多细菌对常规抗生素的耐药问题，并业已成为当今世界卫生面临的最严重的问题之一。目前临床上缺乏抗耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)等耐药革兰氏阳性菌以及抗耐多药革兰氏阴性菌(铜绿假单胞菌)的药物，严重威胁人类健康和生命安全。然而，在过去的四十年中，鲜有创新结构抗生素进入临床实践，因此研发新结构抗菌药物具有重要意义。
近些年，阳离子抗菌肽作为有潜力的抗菌药物显示出了一定的前景。抗菌肽是大多数物种先天免疫的哨兵，是抵御任何感染的第一道防线。不同于大多数通过靶向细胞内细胞器而起作用的抗生素，抗菌肽及其模拟物主要通过引起细胞膜裂解而发挥抗菌作用。因此，不同于常规抗生素由于细菌发生点突变即可使其失去活性的情况，细菌很难对抗菌肽及其模拟物产生耐药性。然而，稳定性差、生产成本高、系统毒性大等问题限制了阳离子抗菌肽的临床应用。因此，很多研究组致力于发展新的策略以解决抗菌肽所面临的这些问题。模拟抗菌肽结构及作用机制而发展抗菌肽模拟物就是其中一个重要的策略，引起了越来越多研究者的关注。
尽管当前抗菌肽的大分子模拟物比较丰富，但是成功发展抗菌肽小分子模拟物的案例并不多。主要是由于这些化合物的设计多注重了结构，而忽略了其结构复杂性、合成步骤繁多、生产成本高及分子不能被蛋白酶降解的肽键的存在对其应用的限制。因此，结构简单、易于合成、生产成本低、不易诱导细菌耐药性的抗菌肽模拟物才有更好的临床应用潜力。
发明内容
本发明的目的在于克服现有技术的至少一个不足，提供小分子抗菌肽模拟物及其应用。
本发明所采取的技术方案是：
本发明的第一个方面，提供：一种小分子抗菌肽模拟物，所述小分子抗菌肽模拟物基于半胱氨酸骨架结构，通过在氨基端、羧基端、或侧链巯基基团进行化学修饰得到，所述小分子抗菌肽模拟物的结构通式如下：
式中：
R1选自 中的一种；
R2选自
中的一种；
R3选自 中的一种。
在一些小分子抗菌肽模拟物的实例中，R1选自 中的一种；
R2选自
中的一种；
R3选自
在一些小分子抗菌肽模拟物的实例中，其结构式为式1、5～12、15～18、20、23、25、、27～30、32～35中的一种：
本发明的第二个方面，提供：一种组合物，其活性成分包括本发明第一个方面所述小分子抗菌肽模拟物中的至少一种。
在一些组合物的实例中，还包括可接受的载体。
在一些组合物的实例中，其剂型为口服剂、注射剂、粘膜给药制剂、外用制剂。
本发明的第三个方面，提供：本发明第一个方面所述小分子抗菌肽模拟物在制备抗感染药物中的应用。
在一些应用的实例中，所述感染由细菌或真菌引起。
在一些应用的实例中，所述细菌或真菌为耐药性细菌或真菌。
在一些应用的实例中，所述耐药性细菌或真菌选自耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌。
本发明的有益效果是：
本发明一些实例的小分子抗菌肽模拟物，可以引起细胞膜去极化、破坏细胞膜完整性，能快速杀菌，可抑制生物膜形成，具有一定的生物膜清除活性，且不易诱导细菌耐药性，具有良好的抗革兰氏阳性菌的活性，对耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)等耐药菌表现出了良好的抗菌活性，可以解决当下抗耐药菌药物缺乏的问题，具有替代或辅助当前临床用抗生素治疗各种耐药菌引起的感染性疾病，可用于敏感菌及耐药菌引起的感染性疾病的治疗，具有高效抗菌活性、低毒性、不受传统耐药机制影响。
本发明一些实例的小分子抗菌肽模拟物的合成方法简单，原料简单易得，操作方法简便。
附图说明
图1为化合物1-35在浓度为4×MIC时对金黄色葡萄球菌膜去极化实验结果。
图2为浓度为4×MIC化合物1-35在与金黄色葡萄球菌共孵育30分钟，然后加入碘化丙啶(PI)避光孵育15分钟后，金黄色葡萄球菌PI阳性率结果。
图3为化合物1-35对金黄色葡萄球菌的杀菌动力学实验结果。0.9％的生理盐水和万古霉素分别用作阴性对照和阳性对照。
图4为生物膜抑制实验结果。浓度为4×MIC的化合物1-35分别与金黄色葡萄球菌共孵育后移除表面浮游细菌，洗涤固定后加入结晶紫溶液染色。除去浮色后加入95％乙醇溶解生物膜中的结晶紫。最后测定OD570处的光吸收值并记录结果。
图5为细菌耐药性实验结果。将金黄色葡萄球菌与1/2×MIC的代表性化合物10,28和33，氨苄西林，环丙沙星共培育，16h后，取有细菌生长的最高药物浓度的菌液，培养至对数期后，进行阶段性MIC测定。共测定21代。
图6为对照组和药物处理后的小鼠肺脏变化结果。选取实验用小鼠，将其分为模型组、万古霉素(Vanc)组、化合物10,28和33给药组和空白对照组共六组。处理后将不同组的小鼠进行解剖，并观察其肺部变化。
图7为化合物10,28和33体内抗菌结果。化合物10,28和33治疗组，万古霉素治疗对照组，空白对照组，及非治疗模型组(MD)肺研磨，涂板培养24小时后菌落计数结果。
具体实施方式
下面结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。
本发明中所用仪器：
高效液相色谱仪为美国waters公司提供的Delta 600型，所用制备柱为反相C18柱(XBridge BEH 130Prep),19mm*250mm；分析柱为反相C18柱，4.6mm*250mm；质谱仪为BrukerMaxis 4G质谱仪；核磁共振谱仪为Bruker AVANCE III HD 400：试剂有：N-A-Fmoc保护的氨基酸、N-羟基苯并三氮唑(HOBt)、氧-苯并三氮唑-N,N,N’,N’-四甲基脲-六氟磷酸盐(HBTU)、二异丙基乙胺(DIEA)和三异丙基硅烷(TIS)均购自上海吉尔生化有限公司；二氯甲烷、N，N-二甲基甲酰胺(DMF)、六氢吡啶(哌啶)、甲醇、三氟乙酸(TFA)、苯酚和吡啶均购自天津第二试剂厂。其它所用仪器或试剂未注明生产厂商者，均为可以通过市购获得的常规产品。实施例中未注明具体条件者，按照常规条件或制造商建议条件进行。
实施例1：化合物1-16的合成
化合物1-13的合成路线如下：
在典型的反应中，市售的氨基酸Fmoc-Cys(R)-OH(0.5mmol，1eq)，HOBT(0.6mmol，81.08mg，1.2eq)，HBTU(0.6mmol，227.54mg，1.2eq)和DIEA(1.2mmol，155.1mg，2.4eq)加入30mL的DMF中，搅拌溶解，加入N-Boc-Ethylenediamine(0.6mmol，96.13mg，1.2eq)在室温下搅拌3h。反应结束后，加入60mL水，60mL乙酸乙酯震荡洗涤，保留有机相，然后使用盐水清洗有机层，使用无水硫酸钠干燥，然后减压蒸发有机相，以95％以上的产率获得中间产物。获得的中间产物无需进一步的处理，加入三氟乙酸(8mL)，二氯甲烷(20mL)和TIS(200μL)搅拌3h(其中化合物8k处理时不加入TIS)，减压脱除溶剂，并加入冰乙醚沉淀目标产物，通过进一步的HPLC纯化，获得最终的化合物1-11。将这一步骤获得的部分产物取(0.3mmol，1eq)与1H-吡唑-1-甲脒盐酸盐(0.36mmol，1.2eq)溶解于10ml DMF中，室温滴加DIEA(0.6mmol，2eq)，反应3h，加入稀盐酸淬灭，加水稀释后，通过HPLC纯化，冻干得化合物12，13。
化合物14-16的合成路线如下：
fmoc-cys(Trt)-OH(1.7mmol，1g，1eq)溶解在二氯甲烷(40mL)中，加入三氟乙酸(10mL)和TIS(500μL)，室温下搅拌2h，反应结束后，减压去除溶剂，加入冰乙醚沉淀获得中间产物。该化合物无需进一步处理，直接溶解于二氯甲烷(50mL)中，加入DIEA(2.5mL)和Br-R(3.4mmol，2eq)，搅拌16h后通过薄层层析监测反应进程，反应结束后，加入通过减压去除溶剂，通过硅胶柱进行纯化，获得中间产物加入20％TFA(15mL)，获得最终的化合物14-16。
实施例2：化合物17-26的合成
化合物17-26的合成路线如下：
Fmoc-cys(trt)-OH(292mg，0.5mmol，1eq)，HOBT(0.6mmol，81.08mg，1.2eq)，HBTU(0.6mmL，227.54mg，1.2eq)和DIEA(1mmol，2eq，130mg)加入30mL的DMF中，搅拌溶解，加入胺类化合物(0.6mmol，1.2eq)，室温下搅拌两小时，反应结束后，加入60mL水，60mL乙酸乙酯震荡洗涤，保留有机相，然后使用盐水清洗有机层，使用无水硫酸钠干燥，然后减压蒸发有机相，以95％以上的产率获得中间产物及终产物17。上一步骤获得得产物(0.479mmol)溶解于15mL四氢呋喃中，加入哌啶(5mL)，室温下搅拌1h，反应结束后，减压去除溶解，加入冰乙醚沉淀，获得产物21及中间产物。中间产物(0.4mmol，290mg，1eq)溶解于DMF(30mL)中，加入HOBT(0.48mmol，64.89mg，1.2eq),HBTU(0.48mmol，181.92mg，1.2eq),DIEA(0.96mmol，124.07mg，2.4eq),4-Biphenylacetic acid(0.48mmol，101.87mg，1.2eq)在室温下搅拌3h。反应结束后，加入60mL水，60mL乙酸乙酯震荡洗涤，保留有机相，然后使用盐水清洗有机层，使用无水硫酸钠干燥，减压蒸发有机相。获得得化合物无需进一步的处理，加入三氟乙酸(8mL)，二氯甲烷(20mL)搅拌3h(，减压脱除溶剂，并加入冰乙醚沉淀目标产物，通过进一步的HPLC纯化，获得最终的化合物25。化合物25通过与方案1a中相同步骤获得化合物26。第一步获得的中间产物加入20％TFA处理3h获得化合物18-20。将化合物21(0.35mmol，1eq)，HOBT,HBTU,DIEA(0.42mmol，1.2eq)分别与BOC-LYS(BOC)-OH，BOC-SER-OH(0.4mmol)溶解于20mlDMF中，反应3h后按照化合物25的实验步骤处理，获得化合物22，24。
实施例3：化合物27-35的合成
化合物27-35的合成路线如下：
在针管合成仪中加入0.5取代度的二氯树脂(1g)，二氯甲烷(10mL)溶胀树脂5min，通过抽滤出去溶剂，加入二氯甲烷(10mL)，fmoc-cys(Dpm)-OH(763.5mg，1.5mmol，3eq)及DIEA(516.96mg，4mmol，8eq)，反应2小时，抽滤除去溶剂，使用DMF洗涤3次，加入20％哌啶(10mL)反应30min，抽滤去除溶剂，加入DMF洗涤4次，加入dmf(10mL)分别与联苯甲酸，联苯乙酸，哌嗪甲酸，茶碱乙酸，二茂铁甲酸(1mmol，2eq)，HOBT(135.12mg，1mmol，2eq),HBTU(379.25mg，1mmol，2eq)，DIEA(258.48mg，2mmol，4eq)反应1h。抽滤去除溶剂，DMF洗涤三次，二氯洗涤2次，甲醇洗涤两次，二氯洗涤一次，加入20％三氟乙醇(10mL)反应2h，收集溶剂，减压去除溶剂，R基为联苯乙酸的中间产物无需进一步处理，分别与3-(2-aminoethyl)pentane-1,5-diamine(1.25mmol，183.17mg，3eq)2,2'-oxybis(ethan-1-amine)(120mg),2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine)(160mg)溶解于DMF(30mL)中，将HOBT(0.5mmol，67.56mg，1.2eq),HBTU(0.5mmol，189.62mg，1.2eq),DIEA(1.5mmol，193.9mg，3.6eq)及第四步产物(0.417mmol,199.74mg,1eq)溶解于DMF(10mL)中，逐滴上述胺溶液中，超过1h滴完，继续反应2h。反应结束后，减压除去溶剂，通过HPLC纯化，获得化合物27-29。化合物30-35通过类似的反应过程获得。
实施例4.化合物的结构表征
称取脱盐后的粗产物(40mg左右)用20％乙腈/水溶液(5mL)溶解，用滤器过滤后上样，该纯化过程所用的柱子为μ-bondapaktm C18反向柱(19mm×300mm)，用20％-80％乙腈/水溶液梯度洗脱，观察紫外检测仪220nm吸收值，收集主峰，将收集的液体分装置50mL烧杯放入-80℃过夜，然后真空冻干得纯的化合物粉末。所合成的化合物结构和核磁表征如下：
化合物1的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.32(dt,J＝16.2,5.7Hz,1H),7.90(q,J＝7.6,7.0Hz,5H),7.78–7.64(m,3H),7.47–7.26(m,4H),4.44–4.11(m,4H),3.65(s,2H),3.31(dt,J＝13.0,6.4Hz,2H),2.96–2.86(m,2H),2.84(dd,J＝9.1,4.6Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.61,156.00,143.71,140.70,127.64,127.06,125.25,120.10,65.73,57.28,46.62,38.36,36.52,25.93；化合物分子量数据:理论分子量C20H23N3O3S[M+H]+＝386.1460,质谱测定分子量386.1562.反相高效液相色谱(RP-HPLC)测定的化合物纯度为93.92％。
化合物2的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.62(t,J＝6.4Hz,1H),8.27(t,J＝5.7Hz,1H),8.00–7.87(m,5H),7.75(d,J＝7.5Hz,2H),7.70(d,J＝8.3Hz,1H),7.43(td,J＝7.5,1.1Hz,2H),7.34(td,J＝7.5,1.2Hz,2H),4.39–4.28(m,2H),4.24(t,J＝4.1Hz,2H),4.23–4.17(m,2H),3.34(tp,J＝13.7,6.7Hz,2H),2.97(dd,J＝13.8,4.9Hz,1H),2.88(h,J＝6.3Hz,2H),2.74(dd,J＝13.8,9.5Hz,1H),1.87(s,3H)；13C NMR(101MHz,DMSO)δ171.08,155.98,143.78,140.70,127.63,127.04,125.28,120.08,65.72,54.01,46.61,38.32,36.52,35.56,14.98；化合物分子量数据:理论分子量C21H25N3O3S[M+H]+＝400.1617,质谱测定分子量400.1672.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.56％。
化合物3的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.82(t,J＝6.3Hz,1H),8.20(t,J＝5.7Hz,1H),7.90(d,J＝7.5Hz,5H),7.72(dd,J＝17.1,7.9Hz,3H),7.42(td,J＝7.5,1.1Hz,2H),7.37–7.18(m,7H),4.40–4.27(m,2H),4.27–4.16(m,4H),3.47(s,2H),3.37–3.26(m,2H),2.94(dd,J＝13.8,4.9Hz,1H),2.85(q,J＝7.1,6.7Hz,2H),2.73(dd,J＝13.8,9.5Hz,1H)；13C NMR(101MHz,DMSO)δ171.00,170.61,155.99,143.76,140.69,135.96,128.96,128.22,127.63,127.05,126.42,125.33,120.09,65.79,54.64,46.57,42.22,40.31,38.31,36.50,32.38；化合物分子量数据:理论分子量C24H31N3O3S[M+H]+＝442.2086,质谱测定分子量442.2144.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.30％。
化合物4的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.62(t,J＝6.4Hz,1H),8.27(t,J＝5.7Hz,1H),7.95–7.87(m,4H),7.73(dd,J＝17.2,7.9Hz,3H),7.43(td,J＝7.5,1.1Hz,2H),7.34(td,J＝7.5,1.2Hz,2H),4.36–4.21(m,6H),3.34(tp,J＝13.7,6.7Hz,2H),2.97(dd,J＝13.8,4.9Hz,1H),2.88(h,J＝6.3Hz,2H),2.74(dd,J＝13.8,9.5Hz,1H),1.87(s,3H)；13C NMR(101MHz,DMSO)δ171.02,169.67,155.98,143.75,140.69,127.63,127.05,125.33,120.09,65.78,54.67,46.57,38.32,36.51,32.41,22.55；化合物分子量数据:理论分子量C23H28N4O4S[M+H]+＝457.1831,质谱测定分子量457.1929.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.50％。
化合物5的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.62(t,J＝6.4Hz,1H),8.27(t,J＝5.7Hz,1H),7.92(d,J＝6.2Hz,4H),7.73(dd,J＝17.2,7.9Hz,3H),7.43(td,J＝7.5,1.1Hz,2H),7.34(td,J＝7.5,1.2Hz,2H),4.41–4.13(m,8H),3.35(ddt,J＝19.3,13.0,6.7Hz,2H),2.99–2.71(m,4H),1.87(s,3H)；13C NMR(101MHz,DMSO)δ171.02,155.98,143.75,140.69,127.63,127.05,125.33,120.09,65.78,54.67,46.57,40.18,38.32,36.51,32.41,22.55；化合物分子量数据:理论分子量C29H32N4O4S[M+H]+＝533.2144,质谱测定分子量533.2086.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.42％。
化合物6的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.38(t,J＝5.7Hz,1H),7.90(d,J＝7.5Hz,4H),7.88(s,1H),7.75(dd,J＝7.8,3.7Hz,3H),7.66(d,J＝8.1Hz,2H),7.54(d,J＝8.0Hz,2H),7.42(t,J＝7.5Hz,2H),7.32(tt,J＝7.5,1.6Hz,2H),4.44–4.33(m,1H),4.26–4.17(m,3H),3.85(s,2H),3.34(h,J＝6.7Hz,2H),2.84(ddd,J＝23.8,13.0,5.8Hz,3H),2.61(dd,J＝13.6,9.0Hz,1H)；13C NMR(101MHz,DMSO-d6)δ171.04,155.95,143.74(d,J＝4.0Hz),140.69,134.84,127.63,127.03(d,J＝3.4Hz),125.31(d,J＝6.7Hz),120.24,120.08,65.79,54.54,46.59,38.32,36.50,32.99,29.01,25.34,17.47；化合物分子量数据:理论分子量C28H28F3N3O3S[M+H]+＝544.1803,质谱测定分子量544.1840.反相高效液相色谱(RP-HPLC)测定的化合物纯度为95.51％。
化合物7的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.36(t,J＝5.7Hz,1H),7.89(t,J＝8.1Hz,5H),7.74(dd,J＝12.0,7.9Hz,3H),7.42(td,J＝7.5,1.1Hz,2H),7.37–7.28(m,6H),7.24(ddt,J＝8.5,5.1,2.8Hz,1H),4.45–4.34(m,1H),4.24(pd,J＝8.6,7.9,4.0Hz,3H),3.77(d,J＝2.2Hz,2H),3.42–3.24(m,2H),2.87(q,J＝6.3Hz,2H),2.81(dd,J＝13.6,5.5Hz,1H),2.61(dd,J＝13.6,8.8Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.95,155.99,143.75,140.70,138.28,128.84,128.33,127.63,127.06,127.02,126.82,125.35,125.26,120.09,65.80,54.27,46.61,38.36,36.51,35.23,33.07；化合物分子量数据:理论分子量C27H29N3O3S[M+H]+＝476.1930,质谱测定分子量476.2038.反相高效液相色谱(RP-HPLC)测定的化合物纯度为94.06％。
化合物8的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.37(t,J＝5.7Hz,1H),7.89(t,J＝6.9Hz,5H),7.74(dd,J＝10.7,8.0Hz,3H),7.46–7.38(m,2H),7.32(tt,J＝7.5,1.6Hz,2H),7.19(d,J＝7.9Hz,2H),7.10(d,J＝7.8Hz,2H),4.44–4.33(m,1H),4.33–4.23(m,2H),4.20(dt,J＝8.6,4.3Hz,1H),3.72(d,J＝2.3Hz,2H),3.40–3.24(m,J＝6.6Hz,2H),2.87(q,J＝5.9Hz,2H),2.79(dd,J＝13.6,5.5Hz,1H),2.59(dd,J＝13.6,8.8Hz,1H),2.26(s,3H)；13C NMR(101MHz,DMSO-d6)δ170.96,155.98,143.74,140.69,135.91,135.12,128.90,128.76,127.64,127.04(d,J＝4.1Hz),125.31(d,J＝8.6Hz),120.10,65.80,54.24,46.59,38.34,36.49,34.90,32.95,20.63；化合物分子量数据:理论分子量C28H31N3O3S[M+H]+＝490.2086,质谱测定分子量490.2218.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.96％。
化合物9的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.39(t,J＝5.8Hz,1H),7.91(dd,J＝12.4,6.0Hz,5H),7.79–7.70(m,3H),7.42(td,J＝7.5,1.1Hz,2H),7.32(tt,J＝7.5,1.5Hz,2H),7.28–7.17(m,2H),6.89–6.81(m,2H),4.44–4.34(m,1H),4.26–4.19(m,3H),3.71(d,J＝2.4Hz,5H),3.35(h,J＝6.7Hz,2H),2.88(h,J＝6.2Hz,2H),2.80(dd,J＝13.7,5.5Hz,1H),2.60(dd,J＝13.6,8.8Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.98,158.13,155.99,143.75,140.69,129.97,127.63,127.06,125.28,120.09,118.36,115.39,114.47,113.72,65.80,54.96,54.27,46.60,38.33,36.50,34.60,32.94；化合物分子量数据:理论分子量C28H31N3O4S[M+H]+＝506.2035,质谱测定分子量506.2170.反相高效液相色谱(RP-HPLC)测定的化合物纯度为91.33％。
化合物10的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.36(t,J＝5.8Hz,1H),7.89(t,J＝8.0Hz,5H),7.81–7.71(m,3H),7.45–7.39(m,6H),7.35–7.28(m,6H),7.26–7.21(m,2H),5.38(s,1H),4.42–4.32(m,1H),4.23(td,J＝7.1,6.2,4.2Hz,3H),3.32(t,J＝6.5Hz,2H),2.85(p,J＝6.1Hz,2H),2.72(dd,J＝13.4,5.6Hz,1H),2.57(dd,J＝13.4,8.7Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.79,155.93,143.73,141.37,140.68,128.52,128.03,127.97,127.63,127.09,125.34,125.28,120.09,118.45,115.48,65.85,54.18,52.76,46.57,38.31,36.48,33.68；化合物分子量数据:理论分子量C33H33N3O3S[M+H]+＝552.7050,质谱测定分子量552.2386.反相高效液相色谱(RP-HPLC)测定的化合物纯度为92.49％。
化合物11的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.19(t,J＝5.8Hz,1H),7.89(dd,J＝12.1,6.7Hz,5H),7.76(dd,J＝8.2,2.9Hz,2H),7.41(t,J＝7.6Hz,2H),7.37–7.21(m,18H),4.43–4.33(m,2H),4.27–4.19(m,2H),4.03(q,J＝7.5Hz,1H),3.30–3.21(m,2H),2.82(h,J＝6.3Hz,2H),2.45(d,J＝7.2Hz,1H)；13C NMR(101MHz,DMSO)δ170.38,155.65,144.27,143.64,140.68,129.07,128.01,127.63,127.04,126.75,125.34,125.28,120.08,118.58,115.60,65.95,65.84,53.79,46.57,38.28,36.49,33.72；化合物分子量数据:理论分子量C39H37N3O3S[M+H]+＝628.2556,质谱测定分子量628.2636.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.35％。
化合物12的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ7.82(dd,J＝8.0,1.2Hz,2H),7.62(dd,J＝7.7,1.4Hz,2H),7.50(td,J＝7.7,1.2Hz,2H),7.41(td,J＝7.9,1.5Hz,2H),7.34–7.21(m,11H),6.92(s,1H),6.42(d,J＝8.2Hz,1H),6.00(t,J＝3.5Hz,1H),5.89(d,J＝6.6Hz,1H),5.83(d,J＝6.6Hz,1H),5.44–5.39(m,1H),4.99(s,1H),4.47–4.40(m,3H),3.43–3.26(m,4H),2.99–2.88(m,2H).13C NMR(101MHz,DMSO-d6)δ171.58,158.57,156.10,143.62,141.66,141.39,128.66,128.01,127.89,127.40,127.17,125.13,120.00,66.74,61.68,54.96,46.70,40.19,39.56,33.16.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝594.2641,质谱测定分子量594.2702.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.56％。
化合物13的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ7.82(dd,J＝8.0,1.2Hz,2H),7.62(dd,J＝7.7,1.4Hz,2H),7.50(td,J＝7.7,1.2Hz,2H),7.41(td,J＝7.8,1.5Hz,2H),7.36–7.23(m,16H),6.92(s,1H),6.37(d,J＝8.0Hz,1H),6.00(t,J＝3.5Hz,1H),5.89(d,J＝6.6Hz,1H),5.83(d,J＝6.6Hz,1H),5.44–5.39(m,1H),4.46(dt,J＝7.9,4.2Hz,1H),4.42(d,J＝4.8Hz,2H),3.43–3.26(m,4H),2.91(dd,J＝14.9,4.3Hz,1H),2.70(dd,J＝14.9,4.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ171.61,158.57,156.10,144.35,143.62,141.39,128.68,128.36,128.03,127.40,127.17,125.13,120.00,67.55,66.74,54.46,46.70,40.19,39.56,32.51.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝670.2774,质谱测定分子量670.2812.反相高效液相色谱(RP-HPLC)测定的化合物纯度为99.11％。
化合物14的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.36(t,J＝5.7Hz,1H),7.92(dd,J＝21.1,6.4Hz,5H),7.75(d,J＝7.5Hz,2H),7.69(d,J＝8.3Hz,1H),7.43(t,J＝7.4Hz,3H),7.33(tt,J＝7.5,1.6Hz,2H),5.18(td,J＝7.8,3.9Hz,1H),4.41–4.31(m,2H),4.28–4.21(m,2H),4.15(td,J＝8.6,5.5Hz,1H),3.41–3.30(m,2H),3.17(d,J＝7.9Hz,2H),2.86(ddd,J＝13.6,10.4,5.8Hz,3H),2.63(dd,J＝13.6,8.8Hz,1H),1.67(s,2H),1.60(s,2H)；13C NMR(101MHz,DMSO-d6)δ171.04,155.95,143.74(d,J＝4.0Hz),140.69,134.84,127.63,127.03(d,J＝3.4Hz),125.31(d,J＝6.7Hz),120.24,120.08,65.79,54.54,46.59,38.32,36.50,32.99,29.01,25.34,17.47；化合物分子量数据:理论分子量C25H31N3O3S[M+H]+＝454.2086,质谱测定分子量454.2162.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.45％。
化合物15的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.41(t,J＝5.7Hz,1H),7.90(d,J＝7.5Hz,5H),7.76(dd,J＝8.1,2.1Hz,3H),7.66–7.56(m,4H),7.48–7.35(m,7H),7.32(td,J＝7.5,1.2Hz,2H),4.45–4.35(m,1H),4.31–4.21(m,3H),3.87–3.79(m,2H),3.43–3.26(m,J＝6.6Hz,2H),2.92–2.81(m,3H),2.65(dd,J＝13.6,8.9Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.96,156.01,143.75,140.70,139.76,138.67,137.58,129.46,128.89,127.64,127.35,127.07,126.62,126.51,125.36,120.10,118.59,115.62,65.81,54.27,46.61,38.35,36.52,34.85,33.09；化合物分子量数据:理论分子量C33H33N3O3S[M+H]+＝552.2243,质谱测定分子量552.2383.反相高效液相色谱(RP-HPLC)测定的化合物纯度为95.30％。
化合物16的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.41(t,J＝5.7Hz,1H),7.93–7.73(m,11H),7.54–7.45(m,3H),7.45–7.37(m,2H),7.32(t,J＝7.4Hz,2H),4.45–4.35(m,1H),4.32–4.21(m,3H),3.94(d,J＝2.7Hz,2H),3.33(dq,J＝11.3,6.9Hz,2H),2.92–2.87(m,1H),2.82(dd,J＝13.6,5.4Hz,2H),2.62(dd,J＝13.7,8.9Hz,1H)；13CNMR(101MHz,DMSO)δ170.33,170.15,141.32,141.30,139.92,138.25,135.45,129.66,128.88,128.51,128.48,128.04,127.97,127.26,127.09,127.06,126.47,126.40,52.77,52.35,51.89,50.70,41.55,36.55,36.16,33.64；化合物分子量数据:理论分子量C31H31N3O3S[M+H]+＝526.2086,质谱测定分子量526.2224.反相高效液相色谱(RP-HPLC)测定的化合物纯度为99.36％。
化合物17的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ7.88(dd,J＝15.8,6.5Hz,3H),7.75(dd,J＝7.5,2.1Hz,2H),7.69(d,J＝8.7Hz,1H),7.44–7.22(m,19H),4.37–4.28(m,1H),4.28–4.18(m,2H),4.05(td,J＝8.3,6.1Hz,1H),3.37(d,J＝12.5Hz,2H),3.10(q,J＝6.1Hz,2H),2.51–2.22(m,3H)；13C NMR(101MHz,DMSO)δ169.81,155.58,144.28,143.68,140.67,129.08,128.03,127.62,127.04,126.74,125.37,120.07,65.87,65.81,59.55,53.79,46.56,41.50,34.08；化合物分子量数据:理论分子量C39H36N2O4S[M+Na]+＝629.2396,质谱测定分子量629.2490.反相高效液相色谱(RP-HPLC)测定的化合物纯度为95.61％。
化合物18的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ7.98(t,J＝5.7Hz,1H),7.90(d,J＝7.5Hz,2H),7.78(d,J＝8.6Hz,2H),7.80–7.68(m,5H),7.41(td,J＝7.4,2.6Hz,2H),7.35–7.23(m,16H),4.40–4.27(m,1H),4.27–4.15(m,2H),4.02(td,J＝8.4,6.0Hz,1H),3.02(d,J＝6.6Hz,2H),2.76(h,J＝6.0Hz,2H),2.46–2.32(m,2H),1.54–1.35(m,4H)；13C NMR(101MHz,DMSO)δ169.72,155.58,144.27,143.68,140.67,129.07,128.02,127.62,127.03,126.74,125.37,120.07,65.91,65.79,53.86,46.55,38.39,37.96,34.01,25.80,24.31；化合物分子量数据:理论分子量C41H41N3O3S[M+H]+＝656.2869,质谱测定分子量656.2957.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.03％。
化合物19的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.14(t,J＝5.7Hz,1H),8.00–7.49(m,12H),7.50–6.87(m,19H),4.29–4.09(m,4H),3.91(s,2H),3.27(qd,J＝6.8,3.0Hz,2H),2.81(q,J＝6.6Hz,2H),2.68(h,J＝6.4Hz,2H),2.50–2.34(m,2H),1.60–1.44(m,3H),1.30–1.13(m,2H)；13C NMR(101MHz,DMSO)δ171.59,169.67,155.66,144.22,140.68,129.06,128.04,127.65,127.06,126.76,125.30,120.11,65.89,65.81,53.81,52.23,46.53,38.59,38.24,36.37,33.72,31.16,26.57,21.96；化合物分子量数据:理论分子量C45H49N5O4S[M+H]+＝756.3505,质谱测定分子量756.3611.反相高效液相色谱(RP-HPLC)测定的化合物纯度为89.00％。
化合物20的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.37(t,J＝6.0Hz,1H),7.99(d,J＝8.1Hz,1H),7.89(s,2H),7.75(dd,J＝11.1,5.9Hz,5H),7.41(t,J＝7.5Hz,2H),7.35–7.15(m,23H),4.37–4.28(m,1H),4.22(ddt,J＝17.7,9.4,4.0Hz,5H),4.07(td,J＝8.3,5.8Hz,1H),2.69(h,J＝6.4Hz,2H),2.43(qd,J＝11.9,7.1Hz,3H),1.75–1.62(m,1H),1.60–1.49(m,2H),1.49–1.44(m,1H),1.33–1.15(m,2H)；13C NMR(101MHz,DMSO)δ170.97,169.70,155.60,144.20,143.65,140.67,139.04,129.05,128.19,128.03,127.63,127.03,126.95,126.76,125.31,120.09,117.70,114.77,65.90,65.82,53.76,52.35,46.52,41.94,38.59,33.75,31.30,26.51,22.02；化合物分子量数据:理论分子量C50H50N4O4S[M+H]+＝803.3553,质谱测定分子量803.3648.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.87％。
化合物21的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ9.06(t,J＝5.9Hz,1H),8.55–8.28(m,3H),7.40–7.20(m,21H),4.49(dd,J＝15.2,6.3Hz,1H),4.29(dd,J＝15.2,5.3Hz,1H),2.51–2.38(m,3H)；13C NMR(101MHz,DMSO)δ166.75,143.66,138.20,128.93,128.22,128.17,127.42,127.03,126.97,66.16,50.97,42.38,32.22；化合物分子量数据:理论分子量C29H28N2OS[M+H]+＝453.1922,质谱测定分子量453.2123.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.46％。
化合物22的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ9.00–8.69(m,2H),8.22(d,J＝5.4Hz,2H),7.92(q,J＝8.2,5.7Hz,3H),7.40–7.05(m,21H),4.49(p,J＝8.0Hz,1H),4.24(dd,J＝15.6,5.8Hz,1H),3.78(q,J＝5.8Hz,2H),2.68(tt,J＝11.1,5.2Hz,2H),2.37(ddd,J＝33.2,11.4,7.4Hz,2H),1.88–1.60(m,2H),1.50(p,J＝7.7Hz,2H),1.30(q,J＝7.5,6.9Hz,2H)；13C NMR(101MHz,DMSO)δ169.24,168.33,144.08,138.87,138.83,129.00,128.09,126.94,121.42,118.46,115.49,112.52,65.93,65.85,51.98,51.71,42.03,38.81,38.42,38.38,33.46,30.44,26.37,20.97；化合物分子量数据:理论分子量C35H40N4O2S[M+H]+＝581.2872,质谱测定分子量581.2957.反相高效液相色谱(RP-HPLC)测定的化合物纯度为91.70％。
化合物23的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.90(t,J＝5.7Hz,1H),8.44(s,2H),8.08(d,J＝5.7Hz,3H),7.53–7.24(m,16H),3.77(t,J＝6.5Hz,1H),3.48(dt,J＝13.6,6.8Hz,1H),3.33(ddt,J＝13.5,7.9,5.6Hz,1H),2.91(qd,J＝12.4,11.8,5.7Hz,2H),2.51–2.44(m,2H)；13C NMR(101MHz,DMSO)δ167.39,143.65,128.94,128.17,126.98,66.24,51.09,38.01,36.47,31.81；化合物分子量数据:理论分子量C24H27N3OS[M+H]+＝406.1875,质谱测定分子量406.2052.反相高效液相色谱(RP-HPLC)测定的化合物纯度为91.91％。
化合物24的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.89(dd,J＝23.3,8.3Hz,1H),8.68(dt,J＝15.1,6.0Hz,1H),8.17(d,J＝5.2Hz,3H),7.39–7.20(m,20H),4.55–4.45(m,1H),4.34(dt,J＝13.7,6.8Hz,1H),4.20(ddd,J＝14.8,8.9,5.6Hz,1H),3.87(ddd,J＝14.9,11.3,5.3Hz,1H),3.67(dd,J＝11.3,6.5Hz,1H),2.52–2.36(m,3H)；13C NMR(101MHz,DMSO)δ169.05,166.69,144.11,138.79,129.02,128.16,128.07,126.99,126.96,126.81,65.90,60.35,53.99,51.92,42.04,33.73；化合物分子量数据:理论分子量C32H33N3O3S[M+H]+＝540.2243,质谱测定分子量540.2456.反相高效液相色谱(RP-HPLC)测定的化合物纯度为99.02％。
化合物25的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.54(d,J＝8.1Hz,1H),8.25(t,J＝5.7Hz,1H),7.86(s,2H),7.70–7.53(m,5H),7.50–7.24(m,20H),4.33(td,J＝7.8,6.0Hz,1H),3.72–3.45(m,2H),3.30(dq,J＝12.8,6.7Hz,2H),2.89–2.76(m,2H),2.44–2.35(m,2H)；13C NMR(101MHz,DMSO)δ172.63,170.27,170.11,144.22,139.97,139.93,138.28,135.40,129.68,129.02,128.87,128.01,127.24,126.72,126.49,126.39,118.09,115.15,65.76,51.62,41.60,38.25,36.43,33.86；化合物分子量数据:理论分子量C38H37N3O2S[M+H]+＝600.2606,质谱测定分子量600.2710.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.54％。
化合物26的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝7.7Hz,1H),7.62–7.58(m,2H),7.58–7.52(m,2H),7.48–7.41(m,2H),7.41–7.36(m,1H),7.36–7.31(m,8H),7.31–7.23(m,10H),6.92(s,1H),6.00(t,J＝3.5Hz,1H),5.89(d,J＝6.6Hz,1H),5.83(d,J＝6.6Hz,1H),4.50(dt,J＝7.7,4.4Hz,1H),3.46(t,J＝1.0Hz,2H),3.42–3.36(m,2H),3.34(ddd,J＝9.8,4.9,1.3Hz,1H),3.32–3.26(m,1H),3.17(dd,J＝14.8,4.4Hz,1H),3.11(dd,J＝14.8,4.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ172.32,171.71,158.57,144.35,140.94,139.06,134.71,130.09,129.09,128.68,128.36,128.13,128.03,127.90,127.27,67.55,54.79,41.47,40.19,39.56,32.53.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝642.2824,质谱测定分子量642.2890.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.56％。
化合物27的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.59(d,J＝8.1Hz,1H),8.20(t,J＝5.7Hz,1H),7.82(s,6H),7.69–7.54(m,4H),7.51–7.17(m,15H),5.34(s,1H),4.46(td,J＝8.0,6.1Hz,1H),3.56(q,J＝14.1Hz,2H),3.19(dhept,J＝19.8,6.5Hz,2H),2.88–2.45(m,12H)；13C NMR(101MHz,DMSO)δ169.24,168.33,144.08,138.87,138.83,129.00,128.09,126.94,121.42,118.46,115.49,112.52,65.93,65.85,51.98,51.71,42.03,38.81,38.42,38.38,33.46,30.44,26.37,20.97；化合物分子量数据:理论分子量C36H43N5O2S[M+H]+＝610.3137,质谱测定分子量610.3359.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.87％。
化合物28的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.58(d,J＝8.5Hz,1H),8.34(t,J＝5.6Hz,1H),8.04(s,3H),7.68–7.61(m,2H),7.59–7.53(m,2H),7.50–7.43(m,2H),7.43–7.34(m,7H),7.34–7.26(m,4H),7.26–7.19(m,2H),5.38(s,1H),4.54(td,J＝8.1,6.0Hz,1H),3.62–3.50(m,4H),3.43(t,J＝5.7Hz,2H),3.26(p,J＝5.7Hz,2H),2.92(t,J＝5.2Hz,2H),2.68–2.60(m,1H),2.59–2.52(m,1H).13C NMR(101MHz,DMSO)δ170.15,170.07,141.39,139.95,138.20,135.53,129.68,128.88,128.48,128.45,128.08,128.00,127.24,127.05,127.01,126.48,126.39,68.72,66.25,52.59,52.22,41.59,40.11,39.95,39.90,39.69,39.48,39.27,39.07,38.86,38.48,33.96.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝568.2556,质谱测定分子量568.2611.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.10％。
化合物29的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.02(d,J＝8.0Hz,1H),7.62–7.52(m,4H),7.48–7.41(m,2H),7.40–7.36(m,1H),7.34–7.27(m,10H),7.27–7.21(m,3H),4.99(s,1H),4.47(dt,J＝8.1,4.9Hz,1H),3.63–3.53(m,6H),3.50(t,J＝3.9Hz,2H),3.46(t,J＝1.0Hz,2H),3.44–3.30(m,2H),3.08–2.97(m,2H),2.84(tt,J＝7.0,3.9Hz,2H),2.27(t,J＝7.0Hz,2H).13C NMR(101MHz,DMSO-d6)δ172.32,171.74,141.66,140.94,139.06,134.71,130.09,129.09,128.66,128.13,128.01,127.90,127.89,127.27,72.88,69.93,69.65,69.61,61.66,55.19,41.61,41.47,40.36,33.17.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝612.2818,质谱测定分子量612.2896.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.44％。
化合物30的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.56(q,J＝6.1Hz,1H),8.01(s,3H),7.44–7.24(m,10H),5.34(d,J＝14.6Hz,1H),4.58–4.41(m,1H),4.30–4.16(m,1H),3.79(ddd,J＝30.4,13.2,3.4Hz,1H),3.52–3.07(m,8H),2.95–2.53(m,5H)；13C NMR(101MHz,DMSO)δ169.73,158.75,141.27,128.56,128.00,127.93,127.89,127.17,53.38,52.85,52.82,51.98,42.35,38.07,36.48,33.95,33.24；化合物分子量数据:理论分子量C24H33N5O2S[M+H]+＝442.2198,质谱测定分子量442.2271.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.89％。
化合物31的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝8.0Hz,1H),8.28(t,J＝5.7Hz,1H),8.03(s,1H),7.89(s,2H),7.42(tt,J＝8.0,1.4Hz,4H),7.33(q,J＝7.5Hz,4H),7.28–7.19(m,2H),5.36(s,1H),5.11(d,J＝16.6Hz,1H),5.03(d,J＝16.5Hz,1H),4.47(td,J＝7.9,5.8Hz,1H),3.45(s,3H),3.33(q,J＝6.6Hz,2H),2.86(h,J＝6.6Hz,2H),2.72(dd,J＝13.4,5.8Hz,1H),2.58(dd,J＝13.4,8.0Hz,1H)；13C NMR(101MHz,DMSO)δ170.18,166.37,154.55,150.93,148.01,143.67,141.27,128.52,128.48,128.04,128.00,127.11,106.43,52.76,52.47,48.19,38.20,36.48,33.37,29.44,27.48；化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝550.2158,质谱测定分子量550.2242.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.97％。
化合物32的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝8.0Hz,1H),7.93–7.87(m,2H),7.66–7.56(m,4H),7.48–7.35(m,3H),7.34–7.21(m,10H),7.18(t,J＝4.8Hz,1H),4.99(s,1H),4.52(dt,J＝8.1,4.6Hz,1H),4.08(t,J＝6.3Hz,2H),3.28(qdt,J＝14.8,4.9,4.0Hz,2H),3.06–2.96(m,4H).13C NMR(101MHz,DMSO-d6)δ172.14,166.98,144.41,141.66,139.46,134.60,129.08,128.74,128.66,128.01,127.91,127.90,127.89,127.71,61.65,55.16,42.27,41.66,33.13.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝510.2137,质谱测定分子量510.2188.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.35％。
化合物33的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.56(d,J＝8.1Hz,1H),8.40(t,J＝5.7Hz,1H),7.90(d,J＝5.9Hz,3H),7.68–7.62(m,2H),7.58–7.56(m,1H),7.51–7.17(m,16H),5.33(s,1H),4.50(td,J＝8.0,5.9Hz,1H),3.65–3.52(m,2H),3.34(t,J＝6.4Hz,2H),2.86(q,J＝5.9Hz,2H),2.70(dd,J＝13.3,5.9Hz,1H),2.57–2.51(m,1H)；13CNMR(101MHz,DMSO)δ171.08,155.98,143.78,143.73,140.70,127.63,127.04,127.02,125.34,125.28,120.08,65.72,54.01,46.61,38.32,36.52,35.56；化合物分子量数据:理论分子量C32H33N3O2S[M+H]+＝524.2293,质谱测定分子量524.2380.反相高效液相色谱(RP-HPLC)测定的化合物纯度为98.80％。
化合物34的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.29(t,J＝5.6Hz,1H),8.04(d,J＝7.9Hz,1H),7.89(s,2H),7.46(dd,J＝17.3,6.9Hz,4H),7.29(dq,J＝34.9,7.0,6.2Hz,7H),5.44(s,1H),4.88(d,J＝9.3Hz,2H),4.62(q,J＝7.4Hz,1H),4.37(s,2H),4.17(s,5H),3.32(d,J＝6.2Hz,2H),2.83(d,J＝15.0Hz,3H),2.67(dd,J＝13.1,8.9Hz,1H)；13C NMR(101MHz,DMSO)δ171.14,169.41,141.45,141.36,128.52,128.03,127.98,127.09,75.66,70.11,69.39,68.65,68.17,52.69,52.10,38.31,36.49,33.25；化合物分子量数据:理论分子量C30H25FeN3O2S[M+H]+＝534.0860,质谱测定分子量534.1123.反相高效液相色谱(RP-HPLC)测定的化合物纯度为96.53％。
化合物35的核磁共振波谱分析数据:1H NMR(400MHz,DMSO-d6)δ8.02(d,J＝8.0Hz,1H),7.59(dd,J＝8.1,1.5Hz,2H),7.58–7.52(m,2H),7.48–7.41(m,2H),7.41–7.21(m,14H),6.92(s,1H),6.00(t,J＝3.5Hz,1H),5.89(d,J＝6.6Hz,1H),5.83(d,J＝6.6Hz,1H),4.99(s,1H),4.47(dt,J＝8.1,4.9Hz,1H),3.46(t,J＝1.0Hz,2H),3.43–3.26(m,4H),3.08–2.97(m,2H).13C NMR(101MHz,DMSO-d6)δ172.32,171.69,158.57,141.66,140.94,139.06,134.71,130.09,129.09,128.66,128.13,128.01,127.90,127.89,127.27,61.66,55.19,41.47,40.19,39.56,33.17.化合物分子量数据:理论分子量C27H31N7O4S[M+H]+＝566.2511,质谱测定分子量566.2560.反相高效液相色谱(RP-HPLC)测定的化合物纯度为97.25％。
实施例5.化合物体外抗菌活性的测定
化合物1-28及对照抗生素的体外抗菌活性的测定所用菌株有：大肠杆菌(E.coli，ATCC25922)、金黄色葡萄球菌(S.aureus，ATCC 29213)、枯草芽孢杆菌(ATCC 23857)、表皮葡萄球菌(ATCC 12228)、白色念珠菌(C.albicans，ATCC 14053)，粪肠球菌(E.faecalis,ATCC 19433),鸡肠球菌(E.gallinarum,ATCC 51299)，以上菌株均为标准菌株，均来自于美国菌种保藏中心。此外，临床分离耐药菌株MSRA S2、MSRA S3、MSRA S4均由兰州大学第一医院提供。
化合物对所测菌株的最小抑菌浓度(MIC)值都是采用美国临床和实验室标准协会(NCCLS)推荐的标准二倍稀释法进行测定的。简单地，取适量细菌或真菌冻存液至新鲜MH/SD培养基中，将菌液置于37℃摇床上，180rpm培养过夜。将上述菌液进行二次转接并在摇床继续培养4-5小时，得到对数生长期细菌。然后取1×105CFU/mL菌液加入96孔板内，每孔100μL，之后按二倍稀释的方式每孔100μL两倍于终浓度的不同浓度的多肽(1-256μM)。阴性对照为新鲜培养液，每个浓度做三个平行。加药后将96孔板放入37℃恒温恒湿培养箱内培养12小时即可观测结果，以肉眼可见显浑浊孔后第一个透亮孔的化合物浓度记为该化合物最小抑菌浓度，即其对该菌的MIC值，结果如表1所示。
表1：化合物1-35对测试菌的最小抑菌浓度MIC(μg/mL)
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由表1可知，化合物1-35对测试菌均表现了良好的抗菌活性，其最小抑菌浓度在1.56μg/mL～125μg/mL。特别是化合物10、25、28、29、32对多种测试菌均具体良好的抑制作用，有望开发为广谱的抑菌剂；化合物5、11、12、17、23、35对多种测试菌均具体良好的抑制作用，对少部分测试菌的抑制作用较差，有望开发为多种测试菌的抑制剂；化合物16、6、7、8、9、15、18、27、33、34同样对多种测试菌均具体良好的抑制作用，对少部分测试菌的抑制作用较差，有望开发为多种测试菌的抑制剂。
实施例6.化合物引起细菌细胞膜去极化
6.1化合物1-35对金黄色葡萄球菌细胞膜膜电位的作用
采用荧光染料DiOC2(3)检测膜电位。膜电位较高时，该染料聚集形成聚合物并在一定波长的光激发产生红色荧光；膜电位较低时，该染料不能聚集可在一定波长的光激发产生绿色荧光，利用红绿荧光相对比例衡量去极化比例。在测试前，先将金黄色葡萄球菌在37℃恒温振荡器中培养至对数期。将对数期的菌1500rpm，离心10min并用PBS洗涤三次，重悬于0.1％的葡萄糖溶液中，控制菌液OD600＝0.5±0.02。然后将菌液加入到96孔黑板，与配好的荧光染料DiOC2(3)37℃共孵育15min后，迅速加入待测化合物，用多功能酶标仪检测荧光变化(激发波长为485nm,发射波长为530nm和630nm)。阴性对照为PBS，阳性对照为1％Triton X-100。
图1显示，化合物1-35均能够对细菌细胞膜产生膜去极化作用，破坏细胞膜电势从而发挥杀菌作用。详细地，在测试菌与荧光染料DiOC2(3)共孵育15分钟后，加入浓度为4×MIC的药物后，用多功能酶标仪检测荧光发现，与PBS处理组相比，化合物1-35同阳性对照1％的Triton X-100一样均能引起降低(图1)，显示化合物1-32与细菌作用后，引起细胞膜去极化破坏其膜电势。
6.2化合物对细菌摄取荧光染料碘化丙啶(PI)的影响
PI是一种DNA结合性染料，能够穿过破损的细胞膜嵌入核酸并释放荧光。该实验用于检测细菌细胞的死亡情况；将浓度为4×MIC的化合物1-35与对数期的金黄色葡萄球菌共孵育30min,然后加入浓度为1mg/mL的PI溶液(终浓度为100μg/mL)，37℃避光孵育15min后，用PBS洗涤后，用流式细胞仪检测PI阳性率。如图2所示，化合物1-35同阳性对照1％TritonX-100一样，均可引起PI进入细胞，这表明化合物1-35可以破坏细胞完整性，会造成细胞内容物外泄继而引起细菌死亡。
实施例7.化合物1-35杀菌动力学测定
采用菌落(CFU)计数法测定了化合物1-35对金黄色葡萄菌S.aureus ATCC 29213杀菌动力学。将对数期浓度为1.0×106CFU/mL的金黄色葡萄球菌加入到96孔板中，然后加入分别加入化合物1-35(终浓度为2×MIC和4×MIC)，37℃共培养，在0、10min、30min、1h,2h,4h,6h,8h,12h的间隔点取出适量菌液稀释至适当倍数后将100μL的稀释的菌液用涂布棒均匀涂布到MH固体培养基上，培养过夜后进行菌落计数。图3显示化合物1-35在2×MIC浓度下，能够在4个小时内杀灭全部细菌，表现了快速杀灭细菌的能力,而阳性对照药物万古霉素在6小时可以杀死测试菌。
实施例8.化合物1-35抗生物被膜(biofilm)作用
采用结晶紫法测定了化合物1-35抑制金黄色葡萄球菌生物膜的形成。将浓度为1.0×106CFU/mL的对数期金黄色葡萄球菌加入到96孔板，然后分别加入浓度为4×MIC的待测化合物1-35，置37℃恒温细菌培养箱静置孵育。24小时后，取出96孔板移除表面浮游细菌，PBS洗涤后用甲醇固定后，加入结晶紫溶液染色15min后，加入95％乙醇溶解生物膜中的结晶紫测定OD570。按公式生物膜形成抑制率(％)＝[1-(实验组OD570-阴性对照组OD570)/(阳性对照组OD570-阴性对照组OD570)]×100％。如图4所示，化合物1-35对生物被膜的形成的抑制率>50％,部分化合物可完全抑制生物被膜的形成。
实施例9.金黄色葡萄球菌对化合物10，28和33耐药性测定
通过连续检测化合物对亚MIC浓度持续处理细菌的MIC值的方法测定化合物持续接触金黄色葡萄球菌后，金黄色葡萄球菌对代表性化合物10，28和33的耐药性，氨苄西林(Ampicillin)、环丙沙星(Ciprofloxacin)用作对照。每次将金黄色葡萄球菌与亚MIC浓度的化合物10，28和33及氨苄西林、环丙沙星共孵育16小时后，取菌液测定MIC，共测21代。图5显示，在进行21天的细菌耐药性实验中，化合物10，28和33的MIC值在1-2倍MIC范围内波动，显示细菌没有对它们产生耐药性；而环丙沙星和氨苄西林对照组分别在处理第18天和处理第17天时发展为原始MIC的640倍，显示了显著的耐药性。
实施例10.化合物10，28和33的体内抗菌活性测定
用MRSA感染的小鼠肺炎模型，检测了化合物10，28和33的体内抗菌活性。选取体重为20g±1g昆明系小鼠(购自兰州大学动物中心)实验室适应培养1周后，随机分组，麻醉后通过气管雾化给菌(25μL浓度为6.0×109CFU/mL的对数期MRSA)建立MRSA感染的小鼠肺炎模型。分别于模型建立2h和12h后，腹腔注射给药。0.9％ NaCl用作阴性对照，万古霉素用作阳性对照。第二次给药24h后，脱臼致死小鼠解剖观察肺部变化，称重后无菌研磨涂板后，涂平板，37℃恒温培养24h后进行菌落计数。如图6所示，感染对照组组与未感染组相比，小鼠肺部发生了明显充血肿大，万古霉素治疗组发生局部的充血，未见明显的肿大。化合物10,28和33治疗组仅发生极轻微的充血，未见明显的肿大。如图7所示，与模型组肺部组织菌落载量相比，万古霉素和化合物10，28，和33(5mg/kg body weight)的治疗组的肺部组织菌落载量发生显著的下降。
综上所述，本发明通过骨架，在半胱氨酸氨基端，羧基端及侧链巯基基团上链接不同疏水基团、阳离子基团的方式改变其两亲性而获得具有治疗敏感菌及耐药菌感染性疾病的小分子抗菌肽模拟物。
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。
Claims (10)
1.一种小分子抗菌肽模拟物，所述小分子抗菌肽模拟物基于半胱氨酸骨架结构，通过在氨基端、羧基端、或侧链巯基基团进行化学修饰得到，其特征在于，所述小分子抗菌肽模拟物的结构通式如下：
式中：
R1选自 中的一种；
R2选自
中的一种；
R3选自 中的一种。
2.根据权利要求1所述的小分子抗菌肽模拟物，其特征在于，R1选自 中的一种；
R2选自 中的一种；
R3选自
3.根据权利要求1所述的小分子抗菌肽模拟物，其特征在于，其结构式为式1、5～12、15～18、20、23、25、、27～30、32～35中的一种：
4.一种组合物，其特征在于，其活性成分包括权利要求1～3任一项所述小分子抗菌肽模拟物中的至少一种。
5.根据权利要求4所述组合物，其特征在于，还包括可接受的载体。
6.根据权利要求4所述组合物，其特征在于，其剂型为口服剂、注射剂、粘膜给药制剂、外用制剂。
7.权利要求1～3任一项所述小分子抗菌肽模拟物在制备抗感染药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述感染由细菌或真菌引起。
9.根据权利要求8所述的应用，其特征在于，所述细菌或真菌为耐药性细菌或真菌。
10.根据权利要求9所述的应用，其特征在于，所述耐药性细菌或真菌选自耐甲氧西林金黄色葡萄球菌、耐万古霉素肠球菌。
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