CN111253322A - 含有n-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用 - Google Patents

含有n-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用 Download PDF

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CN111253322A
CN111253322A CN202010170274.0A CN202010170274A CN111253322A CN 111253322 A CN111253322 A CN 111253322A CN 202010170274 A CN202010170274 A CN 202010170274A CN 111253322 A CN111253322 A CN 111253322A
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side chain
pleuromutilin
nmr
chloroform
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尚若锋
凡媛
刘宇
王学红
郝宝成
梁剑平
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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Abstract

本发明公开了一种含有N‑烷基化嘧啶侧链的截短侧耳素类衍生物及其应用，所述截短侧耳素类衍生物具有如下结构式：
Figure DDA0002408942140000011
式中，R分别为
Figure DDA0002408942140000012
Figure DDA0002408942140000013
或

Description

含有N-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用
技术领域
本发明属于抗菌活性化合物技术领域，尤其涉及一种含有N-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用。
背景技术
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中分离出的一种具有抗菌活性的双萜类化合物。该化合物抑菌活性较低，但通过对该化合物C-14位酯基结构的侧链进行结构改造，可显著提高该类化合物的抑菌活性。通过结构改造，已研发出泰妙菌素、沃尼妙林、瑞他莫林和Lefamulin四种药物。其中，前两种作为兽用药物用于治疗或预防由Brachyspira hyodysenteriae和Mycoplasma spp.引起的疾病。后两种作为人用药物，分别治疗由葡萄球菌和链状球菌引起的伤口感染皮肤感染和社区获得性细菌性肺炎。
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，该类化合物结合在核糖体肽基转移酶(PTC)的V结构域，其中，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，截短侧耳素的分子结构式如式(Ⅰ)所示：
Figure BDA0002408942130000011
发明内容
本发明的目的在于提供一种含有N-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用，所提供的截短侧耳素类衍生物具有显著的抑菌活性。
为实现上述目的，本发明采用的技术方案是：
一种含有N-烷基化嘧啶侧链的截短侧耳素类衍生物，其化学结构式如式(Ⅱ)所示：
Figure BDA0002408942130000021
式中，R分别为
Figure BDA0002408942130000022
Figure BDA0002408942130000023
本发明进一步提供了含有N-烷基化嘧啶侧链的截短侧耳素类衍生物在制备抗菌药物中的应用
优选地，所述含有N-烷基化嘧啶侧链的截短侧耳素类衍生物对多种革兰氏阳性耐药菌具有抑制作用。
优选地，所述革兰氏阳性耐药菌为金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、无乳链球菌或停乳链球菌。
相比于现有技术的缺点和不足，本发明具有以下有益效果：
本发明提供的含有N-烷基化嘧啶侧链的截短侧耳素类衍生物，对多种革兰氏阳性耐药菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、无乳链球菌和停乳链球菌等，具有显著的抑制作用。因此，本发明的截短侧耳素衍生物可以进一步研发为抗菌药物，尤其是抗耐药菌药物。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
一种含有N-烷基化嘧啶侧链的截短侧耳素类衍生物，通过以下技术路线实施制备：
Figure BDA0002408942130000031
本发明对所制得的上述N-烷基化嘧啶侧链的截短侧耳素类衍生物采用IR、NMR和HRMS对其进行结构表征。
实施例1：14-O-[(4-二甲氨基-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,2930,2864,1733,1671,1591,1500,1459,1407,1371,1292,1153,1117,1031,916,807cm-1；1H NMR(400MHz,Chloroform-d)δ6.50(ddd,J＝17.0,11.0,5.7Hz,1H),5.82(s,1H),5.71(d,J＝8.4Hz,1H),5.30(dt,J＝11.0,1.4Hz,1H),5.16(dd,J＝17.4,1.7Hz,1H),3.93–3.75(m,2H),3.58(t,J＝6.1Hz,1H),3.33(dd,J＝10.7,6.5Hz,1H),3.05(s,2H),2.29(dd,J＝11.0,5.4Hz,4H),2.24–2.12(m,2H),2.07(s,1H),1.97(t,J＝8.1Hz,2H),1.76–1.70(m,1H),1.66–1.58(m,2H),1.55–1.35(m,7H),1.25(td,J＝8.2,7.7,2.8Hz,3H),1.11(d,J＝2.4Hz,4H),0.85(d,J＝7.0Hz,3H),0.71(dd,J＝6.8,1.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.00,167.41,158.63,138.22,115.90,97.07,73.55,68.32,57.14,57.14,45.41,44.41,43.43,42.88,40.87,36.17,35.75,34.94,33.46,33.00,29.41,25.87,25.25,23.78,15.83,13.91,13.18,10.41；HRMS(ES)calcd[M+H]+forC29H43N3O4S 530.3044,found 530.3047.
实施例2：14-O-[(4-二乙氨基-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,3082,2930,2864,1732,1 1582,1499,1459,1416,1371,1292,1153,1117,1017,915,807,547cm-1；1H NMR(400MHz,Chloroform-d)δ6.44(dd,J＝17.3,11.1Hz,1H),5.75(s,1H),5.64(d,J＝8.5Hz,1H),5.23(dd,J＝10.9,1.6Hz,1H),5.09(dd,J＝17.5,1.7Hz,1H),3.88–3.68(m,2H),3.50(d,J＝6.3Hz,1H),3.26(dd,J＝10.8,6.6Hz,2H),2.27–2.16(m,4H),2.16–2.07(m,2H),1.99(d,J＝12.2Hz,3H),1.91(dd,J＝14.9,7.6Hz,4H),1.70–1.65(m,1H),1.56(ddt,J＝11.2,8.1,4.1Hz,2H),1.48–1.27(m,7H),1.22–1.14(m,3H),1.04(d,J＝2.9Hz,4H),0.78(d,J＝7.0Hz,3H),0.65(dd,J＝6.9,4.1Hz,3H).；13C NMR(101MHz,Chloroform-d)δ216.05,167.53,158.79,138.22,115.88,97.04,73.55,68.23,59.37,57.15,45.26,44.41,43.40,42.87,40.87,35.77,34.94,33.46,33.08,33.04,29.41,25.87,25.25,23.78,22.83,15.83,13.91,13.18,10.42；HRMS(ES)calcd[M+H]+for C31H47N3O4S 558.3319,found 558.3326.
实施例3：14-O-[(4-吡咯烷基-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,2928,2864,1734,1592,1499,1459,1416,1370,1293,1153,1117,1030,981,915cm-1；1H NMR(400MHz,Chloroform-d)δ6.51(dd,J＝17.4,11.0Hz,1H),5.82(s,1H),5.71(d,J＝8.5Hz,1H),5.30(dd,J＝10.9,1.7Hz,1H),5.16(dd,J＝17.4,1.7Hz,1H),3.94–3.75(m,2H),3.54(s,2H),3.33(dd,J＝10.7,6.4Hz,2H),2.33–2.24(m,4H),2.22–2.11(m,2H),2.06(d,J＝13.1Hz,2H),1.99–1.92(m,3H),1.75(dd,J＝14.6,3.2Hz,1H),1.62(td,J＝11.0,9.1,4.6Hz,2H),1.55–1.37(m,7H),1.32–1.23(m,3H),1.11(s,4H),0.85(d,J＝7.0Hz,3H),0.72(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.05,167.55,158.86,138.33,115.94,97.13,73.65,68.37,59.43,57.24,45.33,44.50,43.53,42.98,40.97,35.86,35.05,33.54,33.11,29.51,25.97,25.35,23.87,22.79,20.09,15.89,13.99,13.26,10.47；HRMS(ES)calcd[M+H]+for C31H45N3O4S 556.3218,found556.3223.
实施例4：14-O-[(4-(3-羟基吡咯烷基)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3386,2928,2863,1718,1592,1498,1456,1417,1370,1294,1220,1153,1117,1019,969,915,806cm-1；1H NMR(400MHz,Chloroform-d)δ6.55–6.42(m,1H),5.85(s,1H),5.74–5.65(m,1H),5.36–5.27(m,1H),5.16(dd,J＝17.4,1.7Hz,1H),3.94–3.80(m,2H),3.73(t,J＝7.0Hz,2H),3.58(s,2H),3.34(s,1H),2.28(s,4H),2.20(dt,J＝9.3,4.5Hz,2H),2.10–2.05(m,2H),1.75(d,J＝12.7Hz,1H),1.66–1.60(m,2H),1.53–1.36(m,7H),1.24(t,J＝7.0Hz,5H),1.11(d,J＝2.6Hz,4H),0.86(d,J＝7.0Hz,3H),0.72(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.06,167.43,159.01,138.37,115.98,97.24,73.64,69.41,68.52,57.23,57.21,53.84,44.50,43.60,43.02,42.98,35.83,35.05,33.53,33.08,32.80,32.76,29.48,25.95,25.36,23.86,22.54,17.48,15.90,13.99,10.47；HRMS(ES)calcd[M+H]+for C31H45N3O5S 572.3131,found 572.3136.
实施例5：14-O-[(4-哌嗪-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,2926,2863,1734,1591,1499,1459,1416,1372,1291,1226,1153,1117,1018,981,915,809cm-1；1H NMR(400MHz,Chloroform-d)δ6.44(dd,J＝17.4,11.0Hz,1H),5.75(s,1H),5.64(d,J＝8.5Hz,1H),5.29–5.22(m,1H),5.09(dd,J＝17.4,1.7Hz,1H),3.85–3.69(m,2H),3.49(s,2H),3.26(dd,J＝10.6,6.6Hz,2H),2.26–2.17(m,4H),2.13(t,J＝7.5Hz,2H),1.99(d,J＝10.4Hz,2H),1.91(dd,J＝15.2,7.9Hz,4H),1.68(dd,J＝14.7,3.2Hz,2H),1.61–1.54(m,2H),1.46–1.28(m,7H),1.19(dd,J＝9.2,6.9Hz,3H),1.04(s,4H),0.78(d,J＝7.0Hz,3H),0.65(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ21.604,167.48,158.74,138.22,115.90,97.05,73.56,68.26,60.86,57.15,45.29,44.42,43.40,42.87,40.87,36.96,35.77,34.94,33.46,33.03,29.41,28.66,25.87,25.24,23.78,22.70,15.83,13.91,10.42；HRMS(ES)calcd[M+H]+for C31H46N4O4S 571.3208,found571.302.
实施例6：14-O-[(4-(4-甲基哌嗪)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3547,2937,2865,1735,1671,1591,1499,1459,1416,1373,1291,1222,1148,1117,1018,980,914,814,700cm-1；1H NMR(400MHz,Chloroform-d)δ6.45(dd,J＝17.4,11.0Hz,1H),5.75(s,1H),5.64(d,J＝8.5Hz,1H),5.27–5.19(m,2H),5.09(dd,J＝17.5,1.7Hz,1H),3.87–3.69(m,2H),3.50(s,2H),3.26(dd,J＝10.9,6.5Hz,3H),2.29–2.10(m,6H),1.99(d,J＝9.6Hz,2H),1.93–1.80(m,4H),1.68(dd,J＝14.6,3.2Hz,1H),1.56(td,J＝10.5,9.8,3.5Hz,2H),1.37(d,J＝7.4Hz,7H),1.23–1.12(m,3H),1.04(s,4H),0.78(d,J＝7.0Hz,3H),0.65(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.09,167.51,158.75,138.19,115.91,97.04,73.53,68.21,57.13,52.41,47.48,45.19,44.40,43.35,42.85,40.85,35.75,34.92,33.46,33.03,29.39,28.68,25.86,25.21,24.28,23.77,22.78,15.83,13.90,10.43；HRMS(ES)calcd[M+H]+for C32H48N4O4S 585.3448,found585.3502.
实施例7：14-O-[(4-吗啉-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3547,2927,2861,1732,1584,1490,1448,1417,1372,1307,1274,1151,1117,1018,984,917,810,552cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),5.97(s,1H),5.64(d,J＝8.5Hz,1H),5.25(dd,J＝11.0,1.6Hz,1H),5.11(dd,J＝17.5,1.6Hz,1H),3.75(d,J＝1.9Hz,2H),3.68(t,J＝4.9Hz,3H),3.51(q,J＝4.8Hz,3H),3.27(dd,J＝10.7,6.5Hz,1H),2.22(d,J＝6.1Hz,4H),2.18–2.07(m,2H),1.99(d,J＝14.3Hz,2H),1.95–1.88(m,1H),1.68(dd,J＝14.4,3.2Hz,1H),1.56(td,J＝10.4,10.0,5.1Hz,2H),1.38(d,J＝16.0Hz,7H),1.25–1.17(m,3H),1.06(s,4H),0.79(d,J＝7.0Hz,3H),0.64(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ215.99,167.30,160.89,138.11,116.08,96.42,73.55,68.49,65.46,59.37,57.13,44.42,43.55,43.18,42.93,40.87,35.74,34.94,33.46,33.05,29.39,25.88,25.33,23.78,20.04,15.84,13.90,13.18,10.42；HRMS(ES)calcd[M+H]+for C31H45N3O5S 572.3169,found 572.3163.
实施例8：14-O-[(4-(3-羟基哌啶)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3442,2933,2862,1732,1584,1494,1447,1417,1373,1308,1274,1151,1117,1018,980,917,807,550cm-1；1H NMR(400MHz,Chloroform-d)δ6.52–6.38(m,1H),6.08(d,J＝1.8Hz,1H),5.68(d,J＝8.3Hz,1H),5.30(d,J＝6.5Hz,2H),5.15(ddd,J＝17.4,5.9,1.6Hz,1H),3.87–3.75(m,3H),3.67(d,J＝10.4Hz,1H),3.48(d,J＝27.7Hz,1H),3.40–3.27(m,2H),2.25(s,4H),2.19(dd,J＝10.5,6.8Hz,2H),2.06(d,J＝15.9Hz,2H),2.02–1.90(m,2H),1.88–1.79(m,1H),1.75(s,1H),1.67–1.61(m,2H),1.54–1.39(m,7H),1.30–1.20(m,3H),1.12(s,4H),0.86(dt,J＝7.0,3.3Hz,3H),0.68(t,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.69,161.61,138.93,116.73,97.24,74.33,71.88,69.37,65.91,57.91,53.14,50.71,45.18,44.36,43.72,41.67,36.52,35.69,34.22,33.81,32.28,30.17,26.62,26.07,24.55,23.66,21.86,16.48,14.67,13.94,11.20；HRMS(ES)calcd[M+H]+for C32H47N3O5S 586.3310,found 586.3316.
实施例9：14-O-[(4-(4-羟基哌啶)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3438,2930,2863,1719,1585,1497,1453,1417,1370,1301,1206,1153,1117,1088,1026,980,915,808,556cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),6.01(s,1H),5.64(d,J＝8.5Hz,1H),5.24(d,J＝10.7Hz,1H),5.10(d,J＝17.4Hz,1H),4.03–3.85(m,3H),3.77(s,2H),3.28–3.17(m,2H),2.21(d,J＝4.7Hz,4H),2.14(q,J＝9.1,8.6Hz,2H),1.99(dd,J＝15.5,2.9Hz,1H),1.95–1.90(m,1H),1.86(s,2H),1.68(d,J＝14.4Hz,1H),1.57(d,J＝11.7Hz,4H),1.47–1.32(m,7H),1.21(d,J＝16.2Hz,3H),1.06(s,4H),0.79(d,J＝7.0Hz,3H),0.64(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.05,167.35,158.29,138.12,116.05,96.41,73.56,68.46,66.31,58.03,57.14,47.56,44.42,43.53,42.93,40.87,40.43,35.76,34.94,33.47,33.03,32.73,31.53,29.41,25.87,25.31,23.78,15.83,13.91,10.43；HRMS(ES)calcd[M+H]+forC32H47N3O5S 586.3310,found 586.3316.
实施例10：14-O-[(4-(3-甲羟基哌啶)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,2931,2862,1732,1585,1496,1445,1418,1308,1207,1179,1117,1019,981,917,882,549cm-1；1H NMR(400MHz,Chloroform-d)δ6.40(dt,J＝10.9,5.8Hz,1H),6.00(d,J＝2.1Hz,1H),5.62(d,J＝8.5Hz,1H),5.24(td,J＝6.7,3.3Hz,1H),5.10(ddd,J＝17.4,5.8,1.7Hz,1H),3.79–3.67(m,2H),3.52–3.44(m,1H),3.45–3.36(m,1H),3.26(d,J＝8.3Hz,1H),3.09–3.01(m,1H),2.18(s,4H),2.16–2.09(m,2H),2.00(d,J＝15.8Hz,3H),1.93(d,J＝7.4Hz,1H),1.79–1.68(m,3H),1.65–1.60(m,1H),1.58–1.51(m,2H),1.37(s,7H),1.30–1.24(m,2H),1.23–1.18(m,3H),1.05(s,4H),0.79(d,J＝6.9Hz,3H),0.66–0.58(m,3H)；13C NMR(101MHz,Chloroform-d)δ216.03,167.66,160.32,138.17,115.94,96.39,73.55,68.56,63.78,59.38,57.13,46.24,44.41,43.46,42.94,42.91,40.90,37.30,35.74,34.89,33.47,29.40,26.14,25.86,25.28,23.77,23.05,22.94,20.04,15.80,13.91,13.18,10.42；HRMS(ES)calcd[M+H]+for C33H49N3O5S 600.3470,found600.3464.
实施例11：14-O-[(4-(4-甲羟基哌啶)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3356,2927,2863,1724,1586,1496,1458,1417,1371,1304,1225,1153,1117,1025,981,911,806,555cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),5.99(s,1H),5.64(d,J＝8.5Hz,1H),5.24(dd,J＝10.8,1.7Hz,1H),5.10(dd,J＝17.5,1.7Hz,1H),4.32(s,1H),3.77(s,2H),3.45(d,J＝5.8Hz,2H),3.27(dd,J＝10.6,6.4Hz,1H),2.84–2.71(m,2H),2.26–2.17(m,4H),2.17–2.09(m,2H),1.97(td,J＝16.1,15.6,5.0Hz,2H),1.76–1.65(m,3H),1.56(ddd,J＝12.5,7.3,2.8Hz,3H),1.48–1.32(m,7H),1.26(d,J＝19.5Hz,2H),1.19–1.10(m,3H),1.06(s,4H),0.79(d,J＝6.9Hz,3H),0.65(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.09,167.44,160.41,138.13,116.03,96.46,73.57,68.41,66.37,57.15,44.43,43.52,43.11,43.06,42.93,40.88,37.84,35.78,34.94,33.47,33.03,29.41,27.26,25.87,25.31,23.79,22.95,15.84,13.91,13.18,10.43；HRMS(ES)calcd[M+H]+for C33H49N3O5S 600.3470,found 600.3464.
实施例12：14-O-[(4-(4-乙羟基哌啶)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3422,2923,2857,1720,1582,1495,1532,1449,1422,1372,1301,1223,1154,1118,1048,1029,971,915,819,551cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),5.97(s,1H),5.64(d,J＝8.5Hz,1H),5.24(dd,J＝11.0,1.6Hz,1H),5.10(dd,J＝17.4,1.7Hz,1H),4.28(s,1H),3.77(s,2H),3.66(t,J＝6.5Hz,2H),3.27(dd,J＝10.4,6.4Hz,1H),2.76(td,J＝12.8,10.8,4.1Hz,2H),2.29–2.17(m,4H),2.16–2.06(m,2H),2.01–1.89(m,2H),1.69(dt,J＝11.5,7.5Hz,4H),1.63–1.49(m,3H),1.48–1.33(m,8H),1.31–1.23(m,2H),1.21–1.10(m,3H),1.06(s,4H),0.79(d,J＝7.0Hz,3H),0.65(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.08,167.45,160.37,138.12,116.02,96.39,73.56,68.39,59.38,59.17,57.15,44.43,43.52,42.93,40.88,38.12,35.78,34.94,33.47,33.03,31.70,30.81,29.41,25.88,25.31,23.79,23.01,20.04,15.84,13.92,13.18,10.42；HRMS(ES)calcd[M+H]+for C34H51N3O5S 614.3553,found 614.3559.
实施例13：14-O-[(4-(4-乙羟基哌嗪)-6-甲基嘧啶-2-基)巯乙酰基]姆体林：
IR(KBr):3448,2929,2864,1734,1591,1499,1459,1415,1347,1292,1225,1153,1117,1018,981,915,807,547cm-1；1H NMR(400MHz,Chloroform-d)δ6.44(dd,J＝17.4,11.0Hz,1H),5.75(s,1H),5.64(d,J＝8.5Hz,1H),5.23(dd,J＝11.0,1.7Hz,1H),5.09(dd,J＝17.5,1.7Hz,1H),3.88–3.69(m,2H),3.50(d,J＝6.4Hz,2H),3.24(td,J＝14.4,12.7,5.7Hz,3H),2.22(d,J＝14.9Hz,4H),2.18–2.11(m,2H),1.99(d,J＝11.2Hz,2H),1.94–1.82(m,4H),1.70–1.64(m,1H),1.60–1.50(m,3H),1.48–1.29(m,7H),1.26–1.15(m,4H),1.04(s,5H),0.78(d,J＝7.0Hz,3H),0.65(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.03,167.49,158.73,138.22,115.89,97.05,73.56,68.26,59.37,57.15,45.26,44.42,43.41,42.88,42.04,40.88,35.77,34.94,33.46,33.03,29.41,28.67,25.87,25.24,24.18,23.78,20.04,15.83,13.91,13.18,10.42；HRMS(ES)calcd[M+H]+for C33H50N4O5S615.3568,found 615.3563.
本发明所制得的截短侧耳素衍生物采用琼脂稀释法测定其对金黄色葡萄球菌ATCC 25923(Staphylococcus aureus ATCC 25923，S.aureus)、耐甲氧西林的表皮球菌ATCC 51625(methicillin-resistant Staphylococcus epidermidis ATCC 51625，MRSE)、耐甲氧西林的金黄色葡萄球菌BNCC 337371(methicillin-resistant Staphylococcusaureus BNCC 337371，MRSA)、无乳链球菌(Streptococcus dysgalactiae，S.dysgalactiae)和停乳链球菌(Streptococcus agalactiae，S.agalactiae)的最小抑菌浓度(MIC)，结果如表1所示：
表1截短侧耳素类衍生物的体外最小抑菌浓度
Figure BDA0002408942130000101
从表1可以看出，所制备的截短侧耳素类衍生物具有良好的体外抑菌活性。其中，所有化合物的MIC要低于对照药物泰妙菌素，大多数化合物的MIC要高于或相当于对照药物瑞他莫林。该类衍生物结构新颖，抑菌活性突出，尤其是甲基嘧啶经N-烷基化后时，能显著增加该类化合的抑菌活性。此外，本发明制备截短侧耳素类衍生物的原料易得、价格低廉，操作简单，产物容易分离、纯化，收率较高。
上述测试说明，本发明制备的含有N-烷基化嘧啶侧链的截短侧耳素类衍生物对多种耐药菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、无乳链球菌和停乳链球菌等，具有显著的抑制作用。因此，本发明的截短侧耳素衍生物可以进一步研发为抗菌药物，尤其是抗耐药菌药物。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (4)

1.一种含有N-烷基化嘧啶侧链的截短侧耳素类衍生物，其特征在于，所示截短侧耳素类衍生物的化学结构式如式(Ⅱ)所示：
Figure FDA0002408942120000011
式中，R分别为
Figure FDA0002408942120000012
Figure FDA0002408942120000013
2.一种如权利要求1所述的含有N-烷基化嘧啶侧链的截短侧耳素类衍生物在制备抗菌药物中的应用。
3.如权利要求2所述的含有N-烷基化嘧啶侧链的截短侧耳素类衍生物的应用，其特征在于，所述含有N-烷基化嘧啶侧链的截短侧耳素类衍生物在抑制多种革兰氏阳性耐药菌药物中的应用。
4.如权利要求3所述的含有N-烷基化嘧啶侧链的截短侧耳素类衍生物的应用，其特征在于，所述革兰氏阳性耐药菌为金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、无乳链球菌或停乳链球菌。
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