CN104803926A - 一种具有嘧啶侧链的截短侧耳素衍生物及其应用 - Google Patents

一种具有嘧啶侧链的截短侧耳素衍生物及其应用 Download PDF

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CN104803926A
CN104803926A CN201510133186.2A CN201510133186A CN104803926A CN 104803926 A CN104803926 A CN 104803926A CN 201510133186 A CN201510133186 A CN 201510133186A CN 104803926 A CN104803926 A CN 104803926A
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pyrimidine
side chain
ethanoyl
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mercapto
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CN104803926B (zh
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尚若锋
衣云鹏
梁剑平
郝宝成
刘宇
郭志廷
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Shandong Qilu King-Phar Pharmaceutical Co., Ltd.
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract

本发明公开一种具有嘧啶侧链的截短侧耳素衍生物，该衍生物具有如下结构式：其中，所述R1为C1-C4烷氧基或羟基；所述R2为氨基或酰氨基；所述R3为氢或C1-C4烷基。本发明的化合物可用于制备抗菌药物，特别是用于制备抗耐甲氧西林金黄色葡萄球菌、抗耐甲氧西林表皮葡萄球菌和/或抗枯草芽孢杆菌药物，抑菌效果优于泰秒菌素。

Description

一种具有嘧啶侧链的截短侧耳素衍生物及其应用
技术领域
本发明属于化学药物领域，具体涉及一种具有嘧啶侧链的截短侧耳素衍生物及其应用。
背景技术
抗生素的发现在人类历史上起了重要的作用。但是，抗生素的滥用导致许多细菌产生了严重的耐药性。耐药菌尤其是葡萄球菌、肺炎链球菌、结核分枝杆菌等，每年引起二百多万人的死亡，严重威胁了人类的健康。因此，研制新的抗耐药菌类药物显得尤为重要。
截短侧耳素(化学结构见式i)是上世纪50年代首次从高等真菌Pleurotusmultilus(Fr.)Sacc.和Pleurotus Passecke‐rianus Pilat中分离了一种具有抗菌活性的双萜类化合物。该化合物由一个含有8个手性中心的5‐6‐8三元环骨架和一个乙醇酸酯的侧链组成。研究表明，截短侧耳素及其衍生物是在核糖体水平上抑制细菌蛋白质的合成，该类化合物作用于细菌核糖体50S亚基的23SRNA上，结合位点在肽基转移酶(PTC)的V结构域。其三元母核结合于A位点的活性口袋中，而侧链部分覆盖了tRNA与核糖体结合的P位点，通过抑制细菌蛋白质的合成而达到抑菌目的。正是由于这种特殊的作用机制，截短侧耳素及其衍生物在体内和体外均有着良好的抗阳性耐药菌的活性，以及较好的药代动力学性质和较低的耐药性。
式i截短侧耳素分子结构式。
截短侧耳素C14的酯基结构侧链是进行化学修饰的主要位点，国内外对截短侧耳素C14的侧链的结构修饰研究一般是在保留酯基结构的前提下，在C22位进行改造，这样能够大大提高其抑菌活性和生物利用度。
截短侧耳素及其衍生物主要是通过抑制肽基转移酶的活性而使蛋白质合成受阻，从而达到抑菌作用。由于该类化合物与目前市场上普遍使用的抗菌药物作用靶点不同，因此，这类药物和其他药物之间不会出现交叉耐药性，尤其对耐药的金黄色葡萄球菌、肺炎链球菌和结核分枝杆菌等有良好的抑制作用。
发明内容
本发明的目的是提供一种具有嘧啶侧链的截短侧耳素新衍生物。
本发明为实现上述目的所采用技术方案如下：
一种具有嘧啶侧链的截短侧耳素衍生物，该衍生物具有如下结构式：
(式I)
或(式II)，
其中，所述R1为C1-C4烷氧基或羟基；所述R2为氨基或酰氨基；所述R3为氢或C1-C4烷基。
进一步，所述酰氨基为C1‐C4烷基酰氨基、取代苯甲酰氨基、哌啶甲酰氨基或
更进一步，所述酰氨基为C1‐C4烷基酰氨基、哌啶甲酰氨基或
进一步，所述取代苯甲酰氨基为卤代苯甲酰氨基、C1‐C4烷基取代苯甲酰氨基或C1‐C4烷氧基取代苯甲酰氨基。
更进一步，所述取代苯甲酰氨基为或
上述各基团中的波浪线表示在结构式I或II中的键合位置。
具体实施方式
以下结合实施例对本发明做进一步详细说明。
实施例1：14-O-[(4-氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将1.65g的4-氨基-6-羟基-2-巯基嘧啶一水合物(10mmol)溶于20mL的甲醇，加入1.1mL浓度为10M的NaOH(11mmol)后搅拌30min。然后逐滴滴加20mL含有5.33g(10mmol)22-O-(4-甲苯磺酰基)氧乙酰基姆体林的二氯甲烷(DCM)溶液，滴加完毕后在室温下搅拌36-40h。减压蒸干溶剂后，粗产物用60mL乙酸乙酯和20mL水的混合溶液溶解，加入50mL饱和NaHCO3后即有大量白色沉淀产生，过滤后用柱层析分离(乙酸乙酯：乙醇＝20:1)即得目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
和
IR(KBr)3368,2930,1729,1629,1575,1542,1457,1286,1117,1019,981,809cm-1；1H NMR(400MHz,CDCl3)δ6.47(dd,J＝17.4,11.1Hz,1H),5.74(d,J＝8.3Hz,1H),5.32(d,J＝11.0Hz,1H),5.24-5.13(m,2H),4.79(s,2H),4.11(q,J＝7.1Hz,1H),3.85(d,J＝16.5Hz,1H),3.69(d,J＝16.5Hz,1H),3.35(d,J＝6.2Hz,1H),2.24(ddd,J＝27.4,15.6,8.1Hz,3H),2.12-1.93(m,3H),1.75(d,J＝14.1Hz,1H),1.63(dd,J＝21.3,11.1Hz,2H),1.54-1.30(m,6H),1.26(dd,J＝14.5,7.2Hz,3H),1.13(s,4H),0.86(d,J＝6.8Hz,3H),0.71(d,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ216.93,166.90,165.97,162.65,160.33,139.23,117.16,84.04,74.59,70.10,60.39,58.10,45.43,43.94,41.85,36.69,36.00,33.25,30.39,26.88,26.34,24.81,21.03,16.79,14.89,11.45；LRMS(ES)calcd[M+H]+for C26H37N3O5S 504.2526,found 504.2520.
附：22-O-(4-甲苯磺酰基)氧乙酰基姆体林的合成
将75.7g(0.2mol)的截短侧耳素、42g(0.22mol)的对甲苯磺酰氯溶于200ml的甲基叔丁基醚(MTBE)中，缓慢搅拌混合物并滴入浓度为0.01mol/ml的NaOH溶液50ml。然后加热至回流，同时剧烈搅拌，10-20min后有大量的白色物质生成，再搅拌20-40min。用布氏漏斗趁热过滤，然后再分别用MTBE和蒸馏水冲洗，自然干燥后得到白色粉末状产物(2)，收率97.8％。
IR(KBr):3446,2924,2863,1732,1633,1597,1456,1371,1297,1233,1117,1035,832,664,560cm-1；1H NMR(400MHz,CDCl3)δ0.63(d,3H,J＝6.8Hz),0.87(d,3H,J＝6.8Hz),1.11–1.15(m,1H),1.22-1.26(s,5H),1.33–1.36(m,1H),1.41–1.44(m,1H),1.46-1.50(m,5H),1.63-1.65(dd,2H,J1＝10Hz,J2＝7.2Hz),2.01–2.08(m,3H),2.21–2.29(m,3H),2.45(s,3H),3.34(d,1H,J＝6.4Hz),4.48(s,2H),5.17-5.21(d,1H,J＝8.8Hz),5.31-5.34(d,1H,J＝6.4Hz),5.75-5.78(d,1H,J＝4.2Hz),6.43(q,1H,J＝17.2Hz,10.8Hz)；7.35-7.37(d,2H,J＝4.0Hz),7.80-7.82(d,2H,J＝4.0Hz)；13C NMR(100MHz,CDCl3)δ216.7,164.8,145.2,138.6,132.5,129.9,127.9,117.2,74.4,70.2,64.9,57.9,45.3,44.4,43.9,41.7,36.4,35.9,34.3,30.2,26.7,26.3,24.7,21.6,16.4,14.6,11.4。
实施例2：14-O-[(4-氨基-6-甲氧基-嘧啶-2-基)巯乙酰基]姆体林
将2.51g的14-O-[(4-氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林(5.0mmol)和2.07g的K2CO3(15mmol)溶于20mL的二甲基甲酰胺(DMF)中，然后分批加入0.71g的碘甲烷(5.0mmol)。在80–85℃条件下搅拌反应4h，冷却反应体系，过滤不溶性的杂质，减压条件下蒸干溶剂。所得的混合物经柱层析分离(石油醚：乙酸乙酯＝1：15)，分别获得1.7g(28％)的14-O-[(4-氨基-6甲氧基-嘧啶-2-基)巯乙酰基]姆体林和3.6g(61％)的14-O-[(1-甲基-4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林。
14-O-[(4-氨基-6-甲氧基-嘧啶-2-基)巯乙酰基]姆体林，结构式如下：
IR(KBr)3374,2928,1732,1626,1585,1548,1390,1307,1273,1212,1152,1117,1048,1017,982,917cm-1；1H NMR(400MHz,DMSO)δ6.66(d,J＝10.8Hz,2H),6.26-5.96(m,1H),5.50(t,J＝13.1Hz,1H),5.42(s,1H),5.19-4.80(m,2H),4.49(d,J＝6.0Hz,1H),3.94-3.81(m,1H),3.75(s,2H),3.62-3.35(m,1H),2.47-2.32(m,1H),2.32-1.96(m,4H),1.71-1.54(m,2H),1.49-0.93(m,13H),0.90-0.68(m,3H),0.58(d,J＝6.8Hz,3H)；13C NMR(100MHz,DMSO)δ217.59,169.52,168.33,168.09,165.63,141.25,115.71,82.04,73.12,70.20,60.23,57.72,53.71,45.43,44.46,42.01,40.66,40.46,40.25,40.04,39.83,39.62,39.41,36.82,34.48,33.69,30.58,28.93,27.10,24.92,21.24,16.56,14.99,11.96；LRMS(ES)calcd[M+H]+for C27H39N3O5S 518.2683,found 518.2681.
实施例3：14-O-[(1-甲基-4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林
14-O-[(1-甲基-4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林制备方法同实施例2，结构式如下：
IR(KBr)3422,2929,1730,1630,1509,1457,1414,1282,1154,1117,1094,807；1H NMR(400MHz,DMSO)δ6.28(s,2H),6.10(dd,J＝17.8,11.2Hz,1H),5.52(d,J＝8.1Hz,1H),5.05(dd,J＝27.5,14.5Hz,2H),4.92(s,1H),4.52(d,J＝5.9Hz,1H),4.34-3.68(m,3H),3.31(d,J＝18.8Hz,4H),2.40(s,1H),2.27-1.88(m,5H),1.83-1.58(m,2H),1.58-1.24(m,8H),1.18(t,J＝7.1Hz,2H),1.05(s,4H),0.82(d,J＝6.8Hz,3H),0.61(d,J＝6.8Hz,3H)；13C NMR(100MHz,DMSO)δ217.55,170.79,166.83,161.88,161.51,160.51,141.22,115.85,81.23,73.13,70.83,60.22,57.65,45.43,44.63,43.90,42.04,40.56,40.30,40.14,39.83,39.62,39.41,36.82,34.56,30.57,29.38,29.07,27.09,24.93,21.23,16.61,14.89,14.56,11.98；LRMS(ES)calcd[M+H]+for C27H39N3O5S 518.2683,found 518.2696.
实施例4：14-O-[(4-乙酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.12g的乙酸(2.0mmol)、0.38g的缩合剂EDCI(2.0mmol)、0.27g的缩合剂HOBt(2.0mmol)和0.39g的N,N-二异丙基乙胺(DIPEA，2.0mmol)溶于15mL的DCM中。搅拌15min后，将0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌32h。反应结束后用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-乙酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林的互变异构体为14-O-[(4-乙酰氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3448,2931,1779,1729,1627,1588,1549,1459,1400,1372,1299,1201,1162,1117,1030,981,939cm-1；1H NMR(400MHz,CDCl3)δ6.47(dd,J＝17.2,11.0Hz,1H),5.73(d,J＝7.9Hz,1H),5.32(d,J＝10.8Hz,1H),5.17(d,J＝17.5Hz,2H),4.69(s,2H),3.85(d,J＝16.4Hz,1H),3.78–3.56(m,3H),3.34(d,J＝4.6Hz,1H),2.16(ddd,J＝75.4,48.8,32.3Hz,5H),1.75(d,J＝13.9Hz,2H),1.63(d,J＝9.1Hz,3H),1.28(dd,J＝45.4,39.0Hz,9H),1.13(s,4H),0.86(d,J＝6.2Hz,3H),0.71(d,J＝6.4Hz,3H)；13C NMR(101MHz,CDCl3)δ216.96,167.08,166.35,162.71,160.59,139.24,117.18,84.18,74.59,70.05,58.41,58.11,45.44,44.32,43.95,42.46,41.86,36.70,36.01,34.45,33.29,30.40,26.89,26.34,24.82,18.43,16.81,14.90,11.47；LRMS(ES)calcd[M+H]+for[C29H41N3O5S 560.2788,found560.2784.
实施例5：14-O-[(4-间氯苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.31g的间氯苯甲酸(2.0mmol)、0.38g的EDCI(2.0mmol)、0.27g的HOBt(2.0mmol)和0.39g的DIPEA(2.0mmol)溶于15mL的DCM中。搅拌15min后，将0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌36h。反应结束后用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-间氯苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(4-间氯苯甲酰氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3368,3215,2931,1735,1625,1586,1547,1459,1283,1240,1116,981,739cm-1；1H NMR(400MHz,CDCl3)δ8.20-7.91(m,2H),7.73-7.34(m,2H),6.49(s,1H),6.08(s,1H),5.72(s,1H),5.21(dd,J＝50.2,22.6Hz,4H),4.11(d,J＝6.7Hz,1H),3.97-3.57(m,2H),3.34(d,J＝6.1Hz,1H),2.40-1.90(m,6H),1.63(td,J＝47.2,13.3Hz,3H),1.42(s,4H),1.36-1.18(m,3H),1.10(s,4H),0.85(d,J＝5.5Hz,3H),0.72(s,3H)；13C NMR(100MHz,CDCl3)δ217.15,170.39,167.95,165.03,164.49,162.37,139.15,134.89,134.19,130.37,130.00,129.70,128.54,117.12,91.07,74.63,69.84,60.42,58.17,45.46,43.98,41.89,36.77,36.00,34.48,34.05,30.43,26.89,26.37,21.05,16.84,14.90,11.45；LRMS(ES)calcd[M+H]+for C33H40ClN3O6642.2399,found 642.2397.
实施例6：14-O-[(4-对甲基苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.26g对甲基苯甲酸(2.0mmol)、0.38g的EDCI(2.0mmol)、0.27g的HOBt(2.0mmol)和0.39g的DIPEA(2.0mmol)溶于15mL的DCM中。搅拌15min后，将0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌40h。反应结束后用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-对甲基苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(4-对甲基苯甲酰氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3375,2930,1735,1624,1586,1458,1298,1255,1166,1117,1071,980,745cm-1；1H NMR(400MHz,CDCl3)δ8.06-7.97(m,2H),7.29(s,1H),6.59-6.36(m,1H),6.09(dd,J＝6.6,3.0Hz,1H),5.72(d,J＝6.3Hz,1H),5.36-5.23(m,1H),5.21-5.06(m,2H),3.91-3.67(m,2H),3.33(s,1H),2.44(d,J＝1.1Hz,2H),2.33-2.01(m,5H),1.74(d,J＝14.5Hz,2H),1.66-1.50(m,3H),1.51-1.18(m,9H),1.16-1.04(m,4H),0.85(d,J＝6.4Hz,3H),0.73(dd,J＝4.3,2.3Hz,3H)；13C NMR(101MHz,CDCl3)δ217.10,170.22,167.98,164.83,163.60,145.16,139.19,130.52,129.39,125.89,117.11,91.10,77.36,77.03,76.72,74.63,69.72,60.40,58.18,45.46,43.98,41.89,36.79,36.01,34.49,34.08,30.45,26.89,26.36,24.84,21.81,21.04,16.84,14.91,11.45；LRMS(ES)calcd[M+H]+for C34H43N3O6S 622.2945,found622.2938.
实施例7：14-O-[(4-对甲氧基苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.30g对甲氧基苯甲酸(2.0mmol)、0.38g的EDCI(2.0mmol)、0.27g的HOBt(2.0mmol)和0.39g的DIPEA(2.0mmol)溶于15mL的DCM中。搅拌15min后，将0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌38h。反应结束后用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-对甲氧基苯甲酰氨基-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(4-对甲氧基苯甲酰氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3369,2933,1734,1605,1581,1549,1511,1458,1401,1299,1251,1160,1116,1069,1024,846cm-1；1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),6.47(dd,J＝17.4,11.0Hz,1H),6.07(s,1H),5.70(d,J＝8.4Hz,1H),5.33-5.22(m,2H),5.14(d,J＝17.4Hz,1H),3.86(d,J＝8.8Hz,3H),3.79-3.61(m,2H),3.32(d,J＝6.2Hz,1H),2.36-1.93(m,5H),1.74-1.50(m,3H),1.47-1.14(m,9H),1.15-1.04(m,4H),0.84(d,J＝6.9Hz,3H),0.71(d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)δ217.16,170.12,168.02,164.87,164.37,163.23,139.16,132.67,120.85,117.09,113.96,91.10,77.38,77.06,76.75,74.61,69.74,58.17,55.57,45.45,44.49,43.97,41.88,36.77,35.99,34.48,34.06,30.43,26.87,26.36,24.82,18.41,16.82,14.90,11.44；LRMS(ES)calcd[M+H]+forC34H43N3O7S 638.2894,found 638.2892.
实施例8：14-O-[(4-(L-哌啶-2-甲酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.26g L-哌啶-2-甲酸(2.0mmol)、0.38g的EDCI(2.0mmol)、0.27g的HOBt(2.0mmol)和0.39g的DIPEA(2.0mmol)溶于15mL的DCM中。搅拌15min后，将0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌42h。反应结束后用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-(L-哌啶-2-甲酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林的互变异构体为14-O-[(4-(L-哌啶-2-甲酰氨基)-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3448,2918,2849,1729,1654,1617,1458,1438,1279,1362,1265,1151,1240,1115,1042,1081,984,957,747cm-1.1H NMR(400MHz,CDCl3)δ6.48(ddd,J＝15.2,11.0,4.2Hz,1H),5.96(s,1H),5.74(t,J＝8.6Hz,1H),5.45-5.16(m,2H),5.15(s,1H),3.91-3.64(m,2H),3.34(d,J＝6.3Hz,1H),2.41-2.14(m,6H),2.05(dd,J＝17.3,9.5Hz,3H),1.82-1.45(m,6H),1.47-1.17(m,9H),1.17-1.01(m,4H),0.85(d,J＝7.0Hz,3H),0.73(t,J＝6.4Hz,3H)；13C NMR(101MHz,CDCl3)δ216.99,170.41,167.89,167.61,164.80,139.28,129.94,128.13,117.06,90.73,77.36,77.04,76.72,74.66,69.73,60.39,58.20,45.48,44.54,44.01,41.92,36.81,36.04,34.49,34.09,30.47,26.93,26.40,24.86,21.41,16.84,16.55,14.91,14.21,11.43；LRMS(ES)calcd[M+H]+for C32H46N4O6S 615.3210,found 615.3213.
实施例9：14-O-[(4-(D-哌啶-2-甲酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将D-哌啶-2-甲酸(2.0mmol)替代实施例8中的L-哌啶-2-甲酸，其余制备过程与实施例8相同，得到目标化合物。
由于羟基和酮式的结构互变性，14-O-[(4-(D-哌啶-2-甲酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林的互变异构体为14-O-[(4-(D-哌啶-2-甲酰氨基)-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3447,1733,1637,1577,1560,1541,1508,1457,1245,1151,1116,969,547cm-1；1H NMR(400MHz,CDCl3)δ6.49(dd,J＝17.2,11.3Hz,1H),5.96(s,1H),5.73(d,J＝8.5Hz,1H),5.25(dd,J＝58.3,14.2Hz,2H),5.01(s,1H),3.79(dd,J＝41.0,16.3Hz,2H),3.35(s,1H),2.27(s,6H),2.06(d,J＝17.5Hz,3H),1.63(d,J＝10.3Hz,6H),1.47-1.19(m,9H),1.14(s,4H),0.86(d,J＝6.8Hz,3H),0.74(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ216.90,170.32,167.87,166.77,164.80,139.22,117.21,117.08,90.78,83.91,77.35,77.24,76.72,74.62,69.70,60.40,58.17,45.46,44.47,43.97,41.88,36.78,36.67,34.48,34.06,30.43,26.90,26.36,24.83,21.42,21.05,16.83,14.89,14.20,11.45；LRMS(ES)calcd[M+H]+forC32H46N4O6S 615.3210,found 615.3202.
实施例10：14-O-[(3-甲基-2(L)氨基丁酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
将0.35g的L-缬氨酸(3.0mmol)溶于由30ml的四氢呋喃(THF)和20ml蒸馏水的混合溶剂中，加入1ml 0.5N的NaOH溶液，在室温搅拌的条件下缓慢滴加0.65g(3.0mmol)的二碳酸二叔丁酯((BOC)2O)。滴加后继续反应9h左右，然后终止反应，减压条件下将THF蒸干后加入20ml乙酸乙酯洗涤，分离两相。水相中加入5％的柠檬酸酸化到pH3-4。产生的白色沉淀过滤后用水洗2-3次，干燥，得到氨基用(BOC)2O保护的L-缬氨酸，备用。
将上述氨基用(BOC)2O保护的L-缬氨酸0.43g(2.0mmol)、0.38g的EDCI(2.0mmol)、0.27g的HOBt(2.0mmol)和0.39g的DIPEA(2.0mmol)溶于15mL的DCM中。搅拌15min后，0.50g的14-O-[(4-氨基-6-酮-嘧啶-2-基)巯乙酰基]姆体林(1.0mmol)加入反应体系中，室温下搅拌46h。反应结束后用饱和NaHCO3和盐水洗涤，再用20mL的三氟乙酸(TFA)和DCM混合溶液(1：1)在室温下搅拌30min，脱去保护剂，蒸干溶剂后，用饱和NaHCO3和盐水洗涤，分离后有机相用无水Na2SO4干燥，过滤后过柱分离(石油醚：乙酸乙酯＝1：2)，获得纯净的目标化合物。
由于羟基和酮式的结构互变性，14-O-[(3-甲基-2(L)氨基丁酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(3-甲基-2(L)氨基丁酰氨基)-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3462,2931,1733,1605,1544,1432,1275,1152,1117,1043,785,547cm-1；1H NMR(400MHz,CDCl3)δ6.48(ddd,J＝15.2,11.0,4.2Hz,1H),5.96(s,1H),5.73(d,J＝8.6Hz,1H),5.40–5.24(m,1H),5.17(d,J＝17.1Hz,3H),4.11(q,J＝7.1Hz,1H),3.92–3.63(m,2H),3.34(d,J＝6.3Hz,1H),2.40-2.13(m,5H),2.05(dd,J＝17.3,9.5Hz,4H),1.69(ddd,J＝11.8,11.2,3.3Hz,5H),1.55-1.20(m,9H),1.13(s,4H),0.85(d,J＝7.0Hz,3H),0.74(d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)δ216.92,167.05,163.88,159.63,157.52,139.20,132.33,130.90,128.84,117.24,94.45,77.36,77.05,76.73,75.38,74.59,70.06,67.78,58.10,45.44,44.37,43.95,41.87,36.72,36.01,34.45,33.24,30.41,26.89,26.27,25.61,24.83,16.86,14.88,11.47；LRMS(ES)calcd[M+H]+for C32H48N4O6S 617.3367,found617.3360.
实施例11：14-O-[(3-甲基-2(D)氨基丁酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林
用D-缬氨酸替代实施例10中的L-缬氨酸，其余制备过程与实施例10相同，得到目标化合物。
由于羟基和酮式的结构互变性，14-O-[(3-甲基-2(D)氨基丁酰氨基)-6-羟基-嘧啶-2-基)巯乙酰基]姆体林互变异构体为14-O-[(3-甲基-2(D)氨基丁酰氨基)-6-酮-嘧啶-2-基)巯乙酰基]姆体林，结构式分别如下：
或
IR(KBr):3463,3363,2922,1731,1604,1544,1433,1278,1152,1117,1042,785.40cm-1；1H NMR(400MHz,CDCl3)δ6.48(dd,J＝17.3,11.0Hz,1H),5.74(d,J＝7.9Hz,1H),5.46(s,1H),5.33(d,J＝10.9Hz,1H),5.23-4.95(m,2H),4.01(dd,J＝14.5,7.4Hz,1H),3.93-3.62(m,2H),3.34(d,J＝6.0Hz,1H),2.42-2.09(m,5H),2.00(dd,J＝15.7,9.6Hz,4H),1.69(ddd,J＝23.1,21.8,14.5Hz,5H),1.57-1.19(m,9H),1.14(s,4H),0.86(d,J＝6.8Hz,3H),0.73(d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)δ216.93,167.03,163.87,159.62,157.51,139.20,132.33,130.91,128.84,117.25,94.41,77.36,77.04,76.72,75.39,74.59,70.05,67.78,58.10,45.44,44.36,43.95,41.86,36.72,36.01,34.45,33.24,30.41,26.89,26.26,25.61,24.83,16.86,14.87,11.47；LRMS(ES)calcd[M+H]+for C32H48N4O6S 617.3367,found617.3361.
抑菌试验
本发明所制得的截短侧耳素衍生物(实施例1-11)采用琼脂稀释法测定其对耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus，MRSA)、耐甲氧西林表皮葡萄球菌methicillin-resistant Staphylococcus epidermidis(MRSE)、枯草芽孢杆菌(S.subtilis)和大肠杆菌(E.coli)的最小抑菌浓度(MIC)，结果见表1。
表1：截短侧耳素类衍生物体外最小抑菌浓度
从上表可以看，实施例1、4和11的化合物对MRSE的抑制效果要优于泰秒菌素，同时实施例1和4的化合物对MRSA的抑制效果也要优于泰秒菌素；实施例2、3和8-11的化合物对枯草芽孢杆菌的抑制效果要优于泰秒菌素。

Claims (6)

1.一种具有嘧啶侧链的截短侧耳素衍生物，所述衍生物具有如下结构式：
其中，所述R1为C1-C4烷氧基或羟基；所述R2为氨基或酰氨基；所述R3为氢或C1-C4烷基。
2.根据权利要求1所述的具有嘧啶侧链的截短侧耳素衍生物，其特征在于，所述酰氨基为C1‐C4烷基酰氨基、取代苯甲酰氨基、哌啶甲酰氨基或
3.根据权利要求2所述的具有嘧啶侧链的截短侧耳素衍生物，其特征在于，所述酰氨基为C1‐C4烷基酰氨基、哌啶甲酰氨基或
4.根据权利要求2所述的具有嘧啶侧链的截短侧耳素衍生物，其特征在于，所述取代苯甲酰氨基为卤代苯甲酰氨基、C1‐C4烷基取代苯甲酰氨基或C1‐C4烷氧基取代苯甲酰氨基。
5.权利要求1所述具有嘧啶侧链的截短侧耳素衍生物在制备抗菌药物中的应用。
6.根据权利要求5所述具有嘧啶侧链的截短侧耳素衍生物在制备抗耐甲氧西林金黄色葡萄球菌、抗耐甲氧西林表皮葡萄球菌和/或抗枯草芽孢杆菌药物中的应用。
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CN111253322A (zh) * 2020-03-12 2020-06-09 中国农业科学院兰州畜牧与兽药研究所 含有n-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用
CN112089715A (zh) * 2020-09-27 2020-12-18 山东齐发药业有限公司 一种畜禽用抗呼吸道阳性菌感染的组合物及其应用
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CN105399684A (zh) * 2015-11-03 2016-03-16 中国农业科学院兰州畜牧与兽药研究所 一种截短侧耳素类化合物、制备方法、多晶型及多晶型的制备方法
CN105622524A (zh) * 2016-03-22 2016-06-01 中国农业科学院兰州畜牧与兽药研究所 截短侧耳素类衍生物及其应用
CN105622524B (zh) * 2016-03-22 2018-03-16 中国农业科学院兰州畜牧与兽药研究所 截短侧耳素类衍生物及其应用
CN109431980A (zh) * 2018-12-27 2019-03-08 山东齐发药业有限公司 一种用于治疗动物皮肤细菌感染的羟啶妙林软膏剂及其制备方法
CN110179802A (zh) * 2019-04-28 2019-08-30 中国农业科学院兰州畜牧与兽药研究所 截短侧耳素类化合物的新用途
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CN112089715A (zh) * 2020-09-27 2020-12-18 山东齐发药业有限公司 一种畜禽用抗呼吸道阳性菌感染的组合物及其应用
CN114853782A (zh) * 2022-06-27 2022-08-05 潍坊医学院 一种具有嘧啶侧链的截短侧耳素衍生物及其制备方法和应用

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