CN105622524B - 截短侧耳素类衍生物及其应用 - Google Patents
截短侧耳素类衍生物及其应用 Download PDFInfo
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Abstract
本发明公开一种新的截短侧耳素类新衍生物,其具有氨基取代的嘧啶杂环侧链,结构式为:其中,R为或R1和R2各自独立的为H或C1‑C4的直链烷基;m为0、1、2或3;n为1、2或3;X为C、N或O;R3为H、OH或NH2。本发明的截短侧耳素类衍生物在体内和体外对多种耐药菌如耐甲氧西林的金黄色葡萄球菌,以及临床中常见的致病菌如金黄色葡萄球菌、枯草杆菌和大肠杆菌有显著的抑制作用,部分衍生物的抑菌活性要优于泰秒菌素,甚至与沃尼妙林相当,具有潜在的医用价值。
Description
技术领域
本发明属于医药化学领域,具体涉及一种具较强抑菌活性的截短侧耳素类新衍生物及其应用。
背景技术
截短侧耳素是上世纪50年代首次从高等真菌Pleurotus multilus(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。该化合物及其衍生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。
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。构效关系表明,C-14位侧链连接一个碱性中心的硫醚基侧链,其衍生物活性就会发生决定性的改进。
由于截短侧耳素及其衍生物的抑菌作用是通过抑制肽基转移酶的活性而使蛋白质合成受阻,从而在核糖体水平上抑制细菌生长,与目前市场上普遍使用的抗菌药物作用靶点不同,而与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
本发明目的在于提供一种具有氨基取代的嘧啶杂环侧链的截短侧耳素类新衍生物。本发明所提供的截短侧耳素类衍生物在细胞水平上具有与延胡索酸泰秒菌素、沃尼妙林等已知药物相当,甚至更高活性。
本发明实现上述目的所提供的截短侧耳素类衍生物具有如下结构式:
其中,R为其中,R1和R2各自独立的为H或C1-C4的直链烷基;m为0、1、2或3;n为1、2或3;X为C、N或O;R3为H、OH或NH2。
本发明所述截短侧耳素类衍生物的制备过程如下:
在碱性条件下,截短侧耳素先与对甲苯磺酰氯反应,反应得到的中间体再与4,6-二氨基2-巯基嘧啶反应得到式I所示的截短侧耳素类衍生物。体系中的中间体可不用分离提纯直接与4,6-二氨基2-巯基嘧啶反应。
其中所述的碱选自:碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、三乙胺、三甲胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-甲基哌啶或N-乙基哌啶中的一种或一种以上混合物。
碱的用量是截短侧耳素摩尔量的1-5倍,更优的用量是截短侧耳素摩尔量的1-3倍。
该步的反应介质为甲醇、乙醇、丙醇、异丙醇、乙二醇、二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、乙酸甲酯、乙腈、四氢呋喃、甲基叔丁基醚、甲基异丁基酮或水中的一种或一种以上的混合溶液。
该步的反应温度为0~90℃,更合适的温度为10~60℃。
截短侧耳素与对甲苯磺酰氯、4,6-二氨基2-巯基嘧啶的摩尔比为(1~2):(1~2):1,更优的摩尔比为(1.05~1.2):(1.05~1.2):1。
式I所示的截短侧耳素类衍生物与氯乙酰氯在碱的作用下经亲核反应制得式II所示的化合物,式II所示的化合物再与胺反应得到其余的截短侧耳素类衍生物。
所述胺具有如下结构式:其中,R1和R2各自独立的为H或C1-C4的直链烷基;m为0、1、2或3;n为1、2或3;X为C、N或O;R3为H、OH或NH2。
其中,所述的碱选自:碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、三乙胺、三甲胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-甲基哌啶或N-乙基哌啶中的一种或一种以上混合物。
碱的用量是式I所示化合物摩尔量的1-5倍,更合适用量是式I所示化合物摩尔量的1.5-3倍。
该步的反应介质为甲醇、乙醇、丙醇、异丙醇、乙二醇、二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、乙酸甲酯、乙腈、四氢呋喃、甲基叔丁基醚、甲基异丁基酮或水中的一种或一种以上的混合溶液。
式I所示的化合物与氯乙酰氯的反应温度为-20~20℃,更合适的温度为-10~10℃。
式II所示的化合物与胺的反应温度为0~90℃,更合适的温度为30~60℃。
式I所示的化合物、氯乙酰氯与胺的摩尔比为1:(1~4):(1~6),式(I)所示的化合物、氯乙酰氯与胺的更合适的摩尔比为1:(1.2~2):(1.2~3)。
所述截短侧耳素类衍生物与盐酸、硫酸、磷酸、甲酸、乙酸、甲磺酸、延胡索酸、枸橼酸、苯磺酸或对甲苯磺酸中的一种或一种以上的酸形成相应的盐。
所述酸的用量为所述截短侧耳素类衍生物摩尔用量的1~10倍,更优选地为2~5倍。反应温度为-10~100℃,更合适的温度为10~60℃。反应在甲醇、乙醇、丙醇、异丙醇、乙二醇、二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、乙酸甲酯、乙腈、四氢呋喃、甲基叔丁基醚、甲基异丁基酮或水中的一种或一种以上的混合溶液进行。
本发明所公开的衍生物合成条件温和,对水、氧气等不敏感;反应原料易得、价格低廉。操作简单,所有的化合物均可以以截短侧耳素为起始原料,采用一锅法制备;产物容易分离、纯化,收率较高,易于工业化生产等优点。
本发明所述截短侧耳素类衍生物及其药学上可接受的盐或溶剂化物在制备抗菌药物中的应用。
所述菌为金黄色葡萄球菌(如耐甲氧西林的金黄色葡萄球菌、非耐药的金黄色葡萄球菌)、枯草杆菌和/或大肠杆菌。
本发明的截短侧耳素类衍生物在体内和体外对多种耐药菌如耐甲氧西林的金黄色葡萄球菌,以及临床中常见的致病菌如金黄色葡萄球菌、枯草杆菌和大肠杆菌有显著的抑制作用,部分衍生物的抑菌活性要优于泰秒菌素,甚至与沃尼妙林相当,具有潜在的医用价值。
具体实施方式
以下对本发明的优选实施例进行说明,应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
14-O-[(4,6-二氨基嘧啶-2-基)巯乙酰基]姆体林(式I):
在250mL的烧瓶中加入3.79g(10mmol)的截短侧耳素、2.1g(11mmol)的对甲苯磺酰氯,加入60mL的二氯甲烷,升温至45℃。搅拌并缓慢滴入浓度为0.01mol/ml的NaOH溶液2.5ml,反应40min后有大量的白色物质生成。降至室温,加入1.44g的4,6-二氨基-2-巯基嘧啶和20mL甲醇,室温搅拌反应36h。反应后减压蒸干溶剂,粗产品用30mL乙酸乙酯和10mL萃取三次,合并有机相,加入30mL饱和的NaHCO3溶液,过滤、获得式I所示化合物(4.77g,收率95%)。
IR(KBr):3475,3377,2933,1728,1619,1582,1547,1465,1309,1153,1117,1019cm-1.
1H NMR(400MHz,DMSO)δ1H NMR(400MHz,DMSO)δ6.20-6.11(m,1H),6.06(d,J=15.9Hz,3H),5.52(d,J=7.8Hz,1H),5.18(d,J=33.9Hz,1H),5.04(dd,J=24.4,14.5Hz,2H),4.50(d,J=5.8Hz,1H),4.03(dd,J=14.1,7.1Hz,1H),3.80(d,J=9.7Hz,1H),3.42(s,1H),2.39(s,1H),2.17(dd,J=25.8,15.3Hz,1H),2.13-1.93(m,4H),1.79-1.53(m,2H),1.51-1.12(m,9H),1.11-0.89(m,4H),0.82(d J=6.5Hz,3H),0.62(d,J=6.4Hz,3H).
13C NMR(101MHz,DMSO)δ217.6,168.3,167.3,163.8,141.2,115.8,79.6,73.1,70.0,60.2,57.7,45.4,44.5,44.0,42.0,36.8,34.5,33.3,30.6,29.0,27.1,24.9,21.2,16.6,15.0,12.0.HRMS(ES)calcd[M+H]+for[C26H38N4O4S 503.2687,found 503.2689.
实施例1:14-O-[(2-(二甲氨基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
在100mL的烧瓶中加入1.51g式I所示化合物,0.61g的N-甲基吗啉和20mL的二氯甲烷,混合物降温至0℃并搅拌,缓慢滴加10mL含有0.51g氯乙酰氯的二氯甲烷溶液,搅拌反应1h。升温至45℃后,滴加加入0.5mL浓度为40%的二甲胺水溶液,加入20mL的甲醇促进两相的溶解,并补加0.61g的N-甲基吗啉。搅拌反应3h后加入30mL饱和的氯化铵溶液洗涤,分离有机相,用水萃取3次,每次10mL,无水硫酸钠干燥过夜,蒸干溶剂后获得的粗产品用柱层析分离(石油醚:乙酸乙酯=1:3),获得0.76g的产品(收率43%)。
IR(KBr):3345,2935,1720,1625,1593,1550,1498,1457,1287cm-1;
1H NMR(400MHz,CDCl3)δ9.36(s,1H),7.09(d,J=15.1Hz,1H),6.51(dd,J=17.4,11.0Hz,1H),5.76(t,J=16.9Hz,1H),5.36-5.14(m,2H),5.04-4.82(m,2H),3.93-3.70(m,2H),3.35(s,1H),3.06(s,1H),2.37-2.30(m,6H),2.25-2.13(m,2H),2.02(dt,J=13.1,12.4Hz,3H),1.79-1.72(m,1H),1.69-1.48(m,4H),1.48-1.42(m,4H),1.38-1.24(m,3H),1.17-1.08(m,4H),0.86(d,J=7.0Hz,3H),0.74(dd,J=15.9,5.4Hz,3H);
13C NMR(101MHz,CDCl3)δ216.03,169.57,167.92,167.15,163.04,155.27,138.26,116.05,86.86,73.60,68.57,62.64,57.16,44.96,44.45,43.51,42.95,40.87,35.79,34.99,33.46,32.86,29.42,25.91,25.37,23.82,15.82,13.89,10.42;HRMS(ES)calcd[M+H]+for[C30H45N5O5S 588.3214,found 588.3219.
实施例2:14-O-[(2-(二乙氨基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用二乙胺替代二甲胺,其余与实施例2相同,收率52%。IR(KBr):3348,2934,1725,1625,1591,1550,1500,1459,1400,1287,1199,1153,1117cm-1;1H NMR(400MHz,CDCl3)δ9.53(d,J=20.9Hz,1H),7.12-7.01(m,1H),6.50(dt,J=20.5,10.3Hz,1H),5.74(d,J=8.5Hz,1H),5.24(ddd,J=18.5,14.2,3.7Hz,2H),4.99(d,J=46.1Hz,2H),3.95-3.64(m,2H),3.35(dd,J=9.2,6.8Hz,1H),3.13(s,1H),2.92(d,J=29.8Hz,1H),2.62(q,J=7.0Hz,3H),2.37-2.27(m,1H),2.27-2.06(m,3H),2.01(dd,J=14.9,7.5Hz,1H),1.73(dd,J=17.5,10.6Hz,1H),1.70-1.47(m,4H),1.44(s,4H),1.39-1.20(m,3H),1.14(t,J=6.7Hz,4H),1.07(t,J=7.1Hz,5H),0.86(d,J=7.0Hz,3H),0.75(d,J=6.9Hz,3H);13C NMR(100MHz,CDCl3)δ216.03,171.03,167.87,167.17,163.04,155.25,138.25,116.06,86.80,73.60,68.55,57.16,47.77,44.45,43.54,42.96,40.87,35.78,34.99,33.47,32.90,29.43,25.90,25.37,23.82,15.83,13.90,11.04,10.43;HRMS(ES)calcd[M+H]+forC32H49N5O5S 616.3527,found 616.3521.
实施例3:14-O-[(2-(吡咯-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用吡咯烷替代二甲胺,其余与实施例2相同,收率49%。IR(KBr):3357,2934,1720,1624,1592,1550,1500,1465,1200,1018,939cm-1;1H NMR(400MHz,CDCl3)δ9.25(s,1H),7.04(d,J=15.2Hz,1H),6.52-6.34(m,1H),5.67(d,J=8.5Hz,1H),5.29-5.07(m,2H),4.90(d,J=25.6Hz,2H),3.83-3.64(m,2H),3.33-3.25(m,1H),3.19(s,1H),2.59(s,4H),2.28-2.20(m,1H),2.19-2.07(m,2H),2.07-1.90(m,3H),1.78(s,4H),1.69(dd,J=14.4,2.4Hz,1H),1.63-1.41(m,4H),1.40-1.33(m,4H),1.23(dt,J=14.5,9.4Hz,3H),1.10-1.01(m,4H),0.80(d,J=7.0Hz,3H),0.66(t,J=13.1Hz,3H);13C NMR(101MHz,CDCl3)δ216.02,169.96,167.86,167.13,163.03,155.34,138.27,116.04,86.88,73.60,68.53,58.96,57.15,53.60,44.45,43.50,42.95,40.87,35.79,34.99,33.46,32.89,29.43,25.90,25.37,23.82,23.08,15.81,13.90,10.43;HRMS(ES)calcd[M+H]+for C32H47N5O5S614.3370,found 614.3371.
实施例4:14-O-[(2-(哌啶-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用哌啶替代二甲胺,其余与实施例2相同,收率47%。IR(KBr):3369,2933,1734,1605,1581,1549,1511,1458,1401,1299,1251,1160,1116,1069,1024,846cm-1;1H NMR(400MHz,CDCl3)δ9.31(d,J=15.1Hz,1H),7.05-6.96(m,1H),6.54-6.37(m,1H),5.66(t,J=8.4Hz,1H),5.28-5.08(m,2H),4.96-4.75(m,2H),3.78-3.64(m,2H),3.34-3.24(m,1H),2.97(s,1H),2.42(s,4H),2.24(dd,J=13.2,6.3Hz,1H),2.19-2.06(m,2H),1.95(dt,J=13.8,12.6Hz,3H),1.68(d,J=14.1Hz,1H),1.61-1.54(m,6H),1.48-1.40(m,3H),1.38(d,J=5.2Hz,4H),1.29-1.18(m,3H),1.11-1.03(m,4H),0.80(d,J=7.0Hz,3H),0.67(dd,J=10.8,4.5Hz,3H);13C NMR(101MHz,CDCl3)δ216.00,169.81,167.88,167.13,163.04,155.29,138.26,116.03,86.85,73.60,68.53,62.03,57.16,53.96,44.45,43.55,42.95,40.87,35.77,34.99,33.46,32.92,29.42,25.90,25.37,24.94,23.81,22.56,15.82,13.90,10.42;HRMS(ES)calcd[M+H]+for C33H49N5O5S 628.3527,found 628.3524.
实施例5:14-O-[(2-(吗啉-4-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用吗啉替代二甲胺,其余与实施例2相同,收率51%。IR(KBr):3422,2919,1719,1637,1547,1500,1466,1287,1118,1047cm-1.1H NMR(400MHz,CDCl3)δ9.26(s,1H),6.99(s,1H),6.44(dd,J=17.4,11.0Hz,1H),5.67(d,J=8.4Hz,1H),5.18(dd,J=58.3,14.2Hz,2H),4.92(s,2H),3.71(dd,J=26.5,17.1Hz,2H),3.29(s,1H),3.03(s,1H),2.81-2.65(m,2H),2.31(dd,J=20.0,10.0Hz,2H),2.27-2.21(m,1H),2.18-2.00(m,3H),2.00-1.92(m,2H),1.87(dd,J=26.1,14.8Hz,3H),1.69(d,J=11.9Hz,1H),1.67-1.61(m,2H),1.60-1.40(m,4H),1.40-1.30(m,4H),1.20(dd,J=18.7,11.5Hz,3H),1.04(d,J=17.7Hz,4H),0.80(d,J=6.8Hz,3H),0.67(d,J=6.8Hz,3H);13C NMR(101MHz,CDCl3)δ216.00,168.67,167.99,167.07,163.05,155.11,138.28,116.04,86.88,73.59,68.57,65.77,61.70,57.14,52.76,44.45,43.54,42.95,40.87,35.76,34.99,33.46,32.91,29.41,25.90,25.39,23.81,15.84,13.91,10.42;HRMS(ES)calcd[M+H]+for C32H47N5O6S 630.3319,found630.3315.
实施例6:14-O-[(2-((3S)-羟基吡咯-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用(3S)-羟基吡咯替代二甲胺,其余与实施例2相同,收率65%。IR(KBr):3448,2930,2930,1724,1629,1593,1549,1500,1466,1287,1150,1118cm-1;1H NMR(400MHz,CDCl3)δ9.34(s,1H),7.08(d,J=15.2Hz,1H),6.49(dt,J=20.0,10.0Hz,1H),5.74(d,J=8.5Hz,1H),5.24(ddd,J=32.5,14.2,4.1Hz,2H),4.99(d,J=29.7Hz,2H),3.82(dt,J=30.8,10.8Hz,2H),3.72(s,1H),3.35(t,J=7.3Hz,1H),3.07(s,1H),2.84(d,J=11.4Hz,2H),2.33(dd,J=13.7,6.9Hz,1H),2.21(dd,J=13.9,10.4Hz,3H),2.10(s,1H),2.07-1.97(m,2H),1.73(dd,J=22.9,11.8Hz,3H),1.63(s,1H),1.58-1.49(m,4H),1.46-1.40(m,4H),1.36-1.24(m,3H),1.18-1.07(m,4H),0.87(d,J=7.0Hz,3H),0.75(d,J=6.9Hz,3H);13CNMR(101MHz,CDCl3)δ216.20,169.56,167.92,167.25,163.09,155.14,138.22,116.06,86.94,73.60,68.63,63.96,61.69,57.16,53.79,44.45,43.52,42.95,40.88,35.76,35.73,34.96,33.48,32.91,32.87,29.42,25.88,25.39,25.07,23.80,23.43,15.87,15.81,13.92,10.42;HRMS(ES)calcd[M+H]+for C32H49N5O6S 630.3320,found 630.3329.
实施例7:14-O-[(2-(4-羟基哌啶-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用4-羟基哌啶替代二甲胺,其余与实施例2相同,收率60%。IR(KBr):3446,3367,2928,2860,1719,1685,1295,1117,1012cm-1;1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.05(s,1H),6.51(dd,J=17.4,11.0Hz,1H),5.74(d,J=8.4Hz,1H),5.25(dd,J=57.9,14.2Hz,2H),4.95(s,2H),3.88-3.69(m,6H),3.41-3.29(m,1H),3.11(s,2H),2.71-2.47(m,4H),2.42-2.27(m,1H),2.27-2.12(m,2H),2.11-1.97(m,2H),1.84-1.68(m,2H),1.67-1.47(m,4H),1.47-1.39(m,4H),1.39-1.19(m,3H),1.18-1.06(m,4H),0.86(d,J=7.0Hz,3H),0.74(d,J=6.9Hz,3H);13C NMR(101MHz,CDCl3)δ216.09,169.39,167.93,167.15,163.06,155.19,138.27,116.05,86.88,73.60,68.57,61.19,59.39,57.16,50.38,44.45,43.53,42.95,40.88,35.77,34.98,33.21,29.42,25.39,23.81,15.83,13.93,13.19,10.43;HRMS(ES)calcd[M+H]+for C33H49N5O6S 644.3476,found 644.3473.
实施例8:14-O-[(2-((3R)-3-羟甲基哌啶-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用(3R)-羟甲基哌啶替代二甲胺,其余与实施例2相同,收率67%。IR(KBr):3448,2930,1720,1625,1593,1550,1500,1466,1400,1286,1201,1153,1117cm-1;1H NMR(400MHz,CDCl3)δ9.33(d,J=5.2Hz,1H),6.98(t,J=8.4Hz,1H),6.42(dd,J=17.3,11.0Hz,1H),5.66(dd,J=8.3,2.3Hz,1H),5.33-5.03(m,2H),4.96(d,J=18.1Hz,2H),3.84-3.63(m,2H),3.58-3.48(m,2H),3.33-3.23(m,1H),3.01(qd,J=16.8,4.6Hz,2H),2.67(dd,J=30.2,10.1Hz,2H),2.23(dd,J=17.0,9.9Hz,3H),2.19-2.06(m,3H),2.05–1.99(m,1H),1.99-1.82(m,3H),1.68(d,J=13.7Hz,2H),1.61(d,J=7.4Hz,1H),1.49(ddd,J=49.0,15.8,7.2Hz,4H),1.40-1.34(m,4H),1.31-1.18(m,3H),1.04(d,J=17.5Hz,4H),0.80(d,J=7.0Hz,3H),0.71-0.60(m,3H);13C NMR(101MHz,CDCl3)δ216.10,169.69,167.87,167.14,163.04,155.27,138.24,116.06,86.88,73.60,68.53,61.67,59.39,57.16,53.36,44.45,43.54,42.94,40.88,38.15,35.76,34.98,33.47,32.93,31.29,30.71,29.42,25.89,25.38,23.81,15.84,13.94,13.19,10.43;HRMS(ES)calcd[M+H]+for C34H51N5O6S658.3628,found 658.3626.
实施例9:14-O-[(2-(4-羟乙基哌啶-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林:
用4-羟乙基哌啶替代二甲胺,其余与实施例2相同,收率74%。IR(KBr):3448,2932,1720,1625,1593,1550,1466,1400,1287,1201,1154,1117,1018cm-1;1H NMR(400MHz,CDCl3)δ9.32(s,1H),6.99(s,1H),6.43(dd,J=17.4,11.0Hz,1H),5.65(d,J=8.4Hz,1H),5.28-5.07(m,2H),4.95(s,2H),4.39(dd,J=6.8,4.8Hz,1H),4.11-3.99(m,1H),3.80–3.61(m,2H),3.28(s,1H),3.24(d,J=4.2Hz,1H),2.94(dd,J=14.7,8.1Hz,1H),2.75(dt,J=17.7,7.5Hz,2H),2.50(dd,J=14.8,8.6Hz,1H),2.30-2.09(m,4H),2.02(s,1H),1.98(s,1H),1.97-1.86(m,1H),1.79(dt,J=13.7,5.8Hz,1H),1.68(d,J=13.9Hz,1H),1.63-1.42(m,4H),1.42-1.35(m,4H),1.30(dd,J=18.2,15.6Hz,2H),1.23-1.12(m,4H),1.09-1.01(m,4H),0.80(d,J=7.0Hz,3H),0.66(d,J=6.9Hz,3H);13C NMR(101MHz,CDCl3)δ216.07,169.52,167.83,167.21,163.09,155.19,138.28,116.04,86.91,73.59,70.41,68.63,62.20,59.39,58.55,57.14,51.95,44.45,42.95,40.88,35.76,34.98,34.21,33.47,29.41,25.90,25.39,23.81,20.03,15.79,13.91,13.19,10.42;HRMS(ES)calcd[M+H]+forC34H53N5O6S 672.3789,found 672.3783.
实施例10:体外抑菌试验
为研究该类衍生物体外对两种耐甲氧西林的金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA,ATCC编号分别为29213和33591)、非耐药的金黄色葡萄球菌(Staphylococcus aureus,S.aureus)、枯草杆菌(Bacillus subtilis,B.subtilis)和大肠杆菌(E.coli)的抑菌活性,进行了MIC(琼脂稀释法)和牛津杯法抑菌圈的测定研究,结果见表1和表2。从实验数据结果可看出这类衍生物均有不同程度的抗菌活性,尤其是MRSA和金黄色葡萄球菌。其中,实施例8化合物的抑菌活性优于对照药物泰秒菌素,甚至和沃尼妙林相当。
表1:受试衍生物的体外最小抑菌浓度
表2.受试衍生物的抑菌圈(mm)测定
表1和2中的前体化合物为:14-O-[(4,6-二氨基嘧啶-2-基)巯乙酰基]姆体林(式I),“--”表示未测试。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.截短侧耳素类衍生物,具有如下结构式:
,化学名称为:14-O-[(2-((3R)-3-羟甲基哌啶-1-基)-乙酰氨基-6-氨基嘧啶-2-基)巯乙酰基]姆体林。
2.权利要求1所述截短侧耳素类衍生物在制备抗菌药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述菌为金黄色葡萄球菌、枯草杆菌和/或大肠杆菌。
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