CN110903272B - 黄酮类化合物及其制备方法和应用 - Google Patents

黄酮类化合物及其制备方法和应用 Download PDF

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CN110903272B
CN110903272B CN201911257926.8A CN201911257926A CN110903272B CN 110903272 B CN110903272 B CN 110903272B CN 201911257926 A CN201911257926 A CN 201911257926A CN 110903272 B CN110903272 B CN 110903272B
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林水木
刘寿平
栗宏霞
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Abstract

本发明涉及黄酮类化合物及其制备方法和应用,该黄酮类化合物具有式(I)所示结构:
Figure DDA0002310809260000011
该黄酮类化合物结构新型,且具有较优的抗菌作用的同时不易产生耐药性,可以用于制备治疗耐药细菌感染的抗菌药物。

Description

黄酮类化合物及其制备方法和应用
技术领域
本发明涉及药物化学技术领域,特别涉及黄酮类化合物及其制备方法和应用。
背景技术
近年来,由于抗菌药物的滥用和错误使用,以及新型抗菌药物的缺乏,细菌的耐药性趋势急剧上升,严重危害公共健康。当前用于耐药细菌感染的治疗方案严重不足,常常伴随着高昂治疗费用,高发病率和高死亡率。考虑到这一严峻形势,世界卫生组织于2017年列出12种对人类健康构成最大威胁的耐药性细菌名单,旨在促进新型抗菌药物的开发;并将细菌耐药性问题列为2019年全球十大健康威胁之一。如果人类对耐药的“超级细菌”的出现没有给予足够的重视,那么由耐药病原体感染引起的死亡人数将急剧增加,将从目前的每年约70万人增加到2050年的每年1000万人。因此,迫切需要开发新型的抗菌药物用于治疗耐药细菌感染。
发明内容
基于此,有必要提供一种黄酮类化合物及其制备方法和应用,该黄酮类化合物结构新型,且具有较优的抗菌作用的同时不易产生耐药性,可以用于制备治疗耐药细菌感染的抗菌药物。
一种黄酮类化合物,具有式(I)所示结构:
Figure BDA0002310809240000011
其中,R1和R2各自独立地选自:C1-30烷基或C2-30烯基;
R3和R4各自独立地选自:氢、C1-30烷基或C2-30烯基,且所述C1-30烷基和C2-30烯基可进一步被一个或多个以下基团取代:卤素、-NR5R6
Figure BDA0002310809240000012
-COR5、-COOR5、-CONR10R11
Figure BDA0002310809240000013
R10和R11各自独立地选自:H、
Figure BDA0002310809240000014
其中,n1为1-10的整数,R14选自H、胍基、-NR5R6
Figure BDA0002310809240000015
R15选自H或C1-6烷基;
R12和R13各自独立地选自:H、
Figure BDA0002310809240000016
其中,n2为1-10的整数,R24选自H、胍基、-NR5R6
Figure BDA0002310809240000017
R25选自H或C1-6烷基;
R22和R23各自独立地选自:H、
Figure BDA0002310809240000021
其中,n3为1-10的整数,R34选自H、胍基、-NR5R6
Figure BDA0002310809240000022
R35选自H或C1-6烷基;
R32和R33各自独立地选自:H或
Figure BDA0002310809240000023
R40为H、胍基、-NR5R6
Figure BDA0002310809240000024
p为1-10的整数;
R5和R6各自独立地选自:H或C1-10烷基,且R5、R6可和与R5、R6相连的N一起形成5-10元杂环或5-10元杂芳环;
R7、R8和R9各自独立地选自:H或C1-10烷基;Y-为阴离子。
上述黄酮类化合物的制备方法,包括以下步骤:
提供式(I-1)所示化合物;
使式(I-1)所示化合物中羟基选择性地进行亲核取代反应,制得式(I)所示化合物;
Figure BDA0002310809240000025
上述黄酮类化合物及其药学上可接受的盐在制备抗菌药物中的应用。
一种抗菌方法,包括实施治疗有效量的上述黄酮类化合物及其药学上可接受的盐。
本发明设计合成了一系列新型的基于山奈酚的黄酮类化合物,它们具有较优的抗菌作用,特别是对革兰氏阳性细菌(包括耐甲氧西林金黄色葡萄球菌)表现出优异的抗菌活性,具有良好的水溶性,优异的成药性,对哺乳动物细胞的毒性低,溶血活性低,膜选择性高,而且制备容易,成本较低。这类抗菌药物具备快速的杀菌性能,能够以浓度依赖性的方式直接破坏细菌细胞膜,从而导致细菌细胞死亡,而且在实验室模拟的耐药性研究中能够克服细菌耐药性的产生。
附图说明
图1为化合物45、化合物52和诺氟沙星对金黄色葡萄球菌ATCC29213的耐药性研究曲线图;
图2为化合物52在金黄色葡萄球菌ATCC29213导致的小鼠角膜感染模型中的体内抗菌功效研究曲线图。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述,并给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
定义和通用术语
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。
本发明中术语“任选地被一个或多个取代基取代”是指被一个或多个取代基取代,或者未取代。具体地,“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“C1-C8烷基任选被一个或多个羟基取代”意味着羟基可以但不必须存在,该说明包括C1-C8烷基被羟基取代的情形和C1-C8烷基不被羟基取代的情形。
“烷基”是指饱和脂肪族烃基,包括直链和支链基团。C1-C6烷基是指含有1至6个碳原子的烷基。非限定性实施例包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。C1-C4烷基是指含有1至4个碳原子的烷基。在一实施例中,C1-C4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代。
本发明的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式存在,即包括溶剂化和非溶剂化形式。
本发明中,被波浪
Figure BDA0002310809240000031
打断的单键代表连接位置,例如:
Figure BDA0002310809240000032
表示丙烷2位的碳为连接位点,
Figure BDA0002310809240000033
表示N为连接位点。本发明中,某可取代位点可被一个或多个取代基取代,且当该可取代位点存在多个取代基时,多个取代基可以彼此相同或不同。
本发明中,某可取代位点可被一个或多个取代基取代,且当该可取代位点存在多个取代基时,多个取代基可以彼此相同或不同。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分。例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
组合物中所含有的赋形剂,可以为一种或多种缓冲剂、稳定剂、抗粘剂、表面活性剂、润湿剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、涂料(肠的或缓释的)防腐剂、抗氧化剂,不透明的剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂。
“可药用的盐”即“医药上可接受的盐”,是指医药上可接受的化合物的有机或无机盐。
当化合物是酸性或包括足够酸性生物电子等排体时,适当的“可药用的盐”指从医药上可接受的包括无机碱和有机碱的无毒碱中制备的盐。该盐衍生自含有铝、铵、钙、铜、铁、铁、锂、镁、锰盐、锰、钾、钠、辛等的无机碱。特定的实施方式包括铵、钙、镁、钾和钠盐。盐衍生自医药上可接受的有机无毒碱,该有机无毒碱包括一级、二级和三级胺的盐、包括自然存在的取代胺的取代胺、环胺和碱性离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N.sup.1-二苄基乙二胺、乙二胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基六氢吡啶、还原葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、赖氨酸、葡甲胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙基胺、三甲胺、三丙胺、氨丁三醇等等。
当化合物是碱性的或包括足够碱性生物电子等排体时,盐可以从医药上可接受的无毒酸中制备,包括无机和有机酸。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸,甲基磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、硫酸、琥珀酸、酒石酸、对甲苯磺酸等等。特定的实施方式包括柠檬酸、氢溴酸、盐酸、磷酸、硫酸、马来酸、酒石酸。其它示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐,硫酸盐,磷酸盐、酸性磷酸盐、异烟酸、乳酸、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、富马酸盐、马来酸盐、龙胆酸盐、葡萄糖酸盐,葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(例如,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。
另外,包含化合物的药物制剂可以为片剂、胶囊剂、口服液体剂、丸剂、颗粒剂、散剂、软膏剂、贴剂、栓剂、口含片、滴眼剂、眼膏剂、眼膏剂、滴耳剂、喷剂、气雾剂、吸入剂、注射剂等。
术语“治疗有效量”是指有效化合物或药物试剂的用量,改善、治愈或治疗疾病或病症的一种或多种症状的必要的最小量。
另外,本发明所述的化合物和药物组合物可单独给药,也可以与其他药剂联合施用。对于与一种以上的活性剂的联合治疗,当该活性剂在分开的剂量制剂中时,该活性剂可以分开施用或联合施用。另外,一种药剂的施用可在另一种药剂施用之前、同时或之后进行。当与其他药剂联合施用时,第二药剂的“有效量”将视所用药物的类型而定。
本发明的化合物或药物组合物也可以包含在试剂盒中。
需要说明的是,本发明未注明具体来源的试剂,为市场购买的常规试剂。
详细说明
一种黄酮类化合物,具有式(I)所示结构:
Figure BDA0002310809240000041
其中,R1和R2各自独立地选自:C1-30烷基或C2-30烯基;
进一步地,R1和R2各自独立地选自:C1-10烷基或C2-10烯基。进一步地,R1和R2各自独立地选自:-C3H7、-C5H7、-C7H15或-C9H19。进一步地,R1和R2各自独立地选自含有一个双键的烯基;更进一步地,C2-10烯基具有
Figure BDA0002310809240000042
结构,c为1-5。更进一步地,R1和R2各自独立地选自
Figure BDA0002310809240000043
R3和R4各自独立地选自:氢、C1-30烷基或C2-30烯基,且C1-30烷基和C2-30烯基可进一步被一个或多个以下基团取代:卤素、-NR5R6
Figure BDA0002310809240000044
-COR5、-COOR5、-CONR10R11
Figure BDA0002310809240000045
进一步地,R3和R4各自独立地选自:氢或C1-6烷基,且C1-6烷基任选进一步被一个或多个以下基团取代:卤素、-NR5R6
Figure BDA0002310809240000046
-COR5、-COOR5、-CONR10R11
Figure BDA0002310809240000047
进一步地,R3和R4不同时为H。
更进一步地,R3和R4中至少有一个中含有氮原子;更进一步地,R3和R4的主链端基为含N的基团;更进一步地,R3和R4中至少有一个含有胍基。更进一步地,R3和R4中至少有一个含有
Figure BDA0002310809240000048
基团,且R40为H、胍基、-NR5R6
Figure BDA0002310809240000049
p为1-10的整数。更进一步地,p为1、2、3、4或5。
R10和R11各自独立地选自:H、
Figure BDA0002310809240000051
进一步地,R10和R11中至少有一个为
Figure BDA0002310809240000052
其中,n1为1-10的整数,进一步地,n1为2、3、4或5;
R14选自H、胍基、-NR5R6
Figure BDA0002310809240000053
R15选自H或C1-6烷基,进一步地,R15为甲基或乙基;
R12和R13各自独立地选自:H、
Figure BDA0002310809240000054
其中,n2为1-10的整数,R24选自H、胍基、-NR5R6
Figure BDA0002310809240000055
R25选自H或C1-6烷基;
R22和R23各自独立地选自:H、
Figure BDA0002310809240000056
其中,n3为1-10的整数,R34选自H、胍基、-NR5R6
Figure BDA0002310809240000057
R35选自H或C1-6烷基;
R32和R33各自独立地选自:H或
Figure BDA0002310809240000058
R40为H、胍基、-NR5R6
Figure BDA0002310809240000059
p为1-10的整数;更进一步地,p为1、2、3、4或5;
R5和R6各自独立地选自:H或C1-10烷基,且R5、R6可和与R5、R6相连的N一起形成5-10元杂环或5-10元杂芳环;
进一步地,R5和R6各自独立地选自:H或C1-6烷基,且R5、R6可和与R5、R6相连的N一起形成5-6元杂环或5-6元杂芳环;
更进一步地,5-6元杂环或5-6元杂芳环为含有N、O和S中至少一种原子的杂环或杂芳环。
R7、R8和R9各自独立地选自:H或C1-10烷基;进一步地,R7、R8和R9各自独立地选自:H或C1-6烷基。更进一步地,R7、R8和R9中有一个为甲基。
Y-为阴离子,进一步地,Y-为卤素阴离子;更进一步地,Y-为碘离子。
在一实施例中,上述黄酮类化合物具有式(II)所示结构:
Figure BDA00023108092400000510
其中,R50为卤素、-NR5R6
Figure BDA00023108092400000511
进一步地,R50为溴、-NR5R6
Figure BDA00023108092400000512
更进一步地,R50为-NR5R6
Figure BDA0002310809240000061
更进一步地,R50为-NR5R6
a为1-15的整数;进一步地,a为3、4、5、6、7、8、9或10。
在一实施例中,上述黄酮类化合物具有式(III)所示结构:
Figure BDA0002310809240000062
b为1、2、3、4或5;进一步地,b为1。
c为1、2、3、4或5;进一步地,c为1。
进一步地,R50选自以下基团:
Figure BDA0002310809240000063
在一实施例中,上述黄酮类化合物具有式(IV)所示结构
Figure BDA0002310809240000064
R3和R4各自独立地选自:氢或C1-6烷基,且所述C1-6烷基可进一步被一个或多个以下基团取代:-COR10、-COOR10、-CONR10R11
Figure BDA0002310809240000065
且R3和R4不同时为氢。
进一步地,R3和R4各自独立地为H、
Figure BDA0002310809240000066
Figure BDA0002310809240000067
且R3和R4不同时为氢;m1为1、2或3;进一步地,m1为1或2;
进一步地,R3和R4各自独立地为H、
Figure BDA0002310809240000068
Figure BDA0002310809240000071
且R3和R4不同时为氢;
其中,n1为1、2、3、4或5;R14选自H、胍基或-NR5R6;进一步地,R14选自胍基或-NR5R6
R15选自H或C1-6烷基;进一步地,R15选自甲基、乙基或丁基;
R12和R13各自独立地选自H、
Figure BDA0002310809240000072
其中,n2为1、2、3、4或5,R24选自H、胍基或-NR5R6;进一步地,R24选自胍基或-NR5R6;R25选自H或C1-6烷基;进一步地,R25选自甲基、乙基或丁基;
R22和R23各自独立地选自H、
Figure BDA0002310809240000073
其中,n3为1、2、3、4或5,R34选自H、胍基或-NR5R6;进一步地,R34选自胍基或-NR5R6;R35选自H或C1-6烷基;进一步地,R35选自甲基、乙基或丁基;
R32和R33各自独立地选自H或
Figure BDA0002310809240000074
R40为H、胍基或-NR5R6,p为1、2、3、4或5;
R5和R6各自独立地选自:H或C1-6烷基,且R5、R6可和与R5、R6相连的N一起形成5-6元杂环或5-6元杂芳环。
更进一步地,5-6元杂环或5-6元杂芳环为含有N、O和S中至少一种原子的杂环或杂芳环。
进一步地,R1、R2、R3和R4中至少一个具有含有氮原子的取代基。
进一步地,黄酮类化合物为两亲性的阳离子型化合物。
进一步地,R1和R2为疏水基团;R3和R4含有亲水基团。
进一步地,黄酮类化合物中至少含有一个胍基。
在一实施例中,上述黄酮类化合物选自以下化合物:
Figure BDA0002310809240000075
Figure BDA0002310809240000081
Figure BDA0002310809240000091
Figure BDA0002310809240000101
Figure BDA0002310809240000111
Figure BDA0002310809240000121
黄酮类衍生物广泛存在于蔬菜和水果中,通常对人体健康有益且无副作用。黄酮衍生物具有多种药理活性,例如抗菌、抗氧化、抗病毒和抗癌活性等,但其药理活性基本都未达到临床应用的程度。山奈酚属于黄酮类化合物,其在蔬菜、水果茶和中草药中含量很高,具有多种生物活性,包括抗炎、抗氧化、抗癌和抗凝活性等。山奈酚提供的黄酮骨架(flavone)具有体积小且刚性强的特点。本发明创新性地通过在黄酮骨架上引入的脂质疏水链,如此可以促进黄酮类化合物插入细菌的磷脂双层膜中,进而使得本发明的黄酮类化合物具有优异的抗菌性,且不易产生耐药性。
进一步地,本发明在黄酮骨架上引入的含N的取代基,从而引入阳离子模块,以提供正电荷和亲水性,可促进黄酮类化合物通过静电作用与带负电荷的细菌细胞膜发生相互作用。由于哺乳动物的细胞膜是电中性的,因此两亲性的阳离子型黄酮衍生物可以提高其在细菌和哺乳动物细胞膜之间的选择性。通过对黄酮衍生物的疏水和阳离子亲水部分的进行一系列优化调整,可以获得高效低毒的膜活性抗菌药物。特别是,化合物52在金黄色葡萄球菌ATCC29213导致的小鼠角膜感染模型中仍然保持优异的抗菌效果。这类基于山奈酚的黄酮类化合物具备新分子实体和新型的抗菌机制,能够有效对抗耐药性细菌感染。
本发明还提供了上述黄酮类化合物的制备方法,包括以下步骤:
S10:提供式(I-1)所示化合物,即山奈酚(3,5,7,4'-四羟基黄酮);
S20:使式(I-1)所示化合物中羟基选择性地进行亲核取代反应,制得式(I)所示化合物;
Figure BDA0002310809240000131
可理解的,步骤S20限定,优选步骤S20包括以下步骤:
S211:使式(I-1)所示化合物和卤代烷烃或卤代烯烃发生取代反应,生成式(I-2)所示化合物;
Figure BDA0002310809240000132
进一步地,步骤S211为:使式(I-1)所示化合物和碘代烷烃(如C3H7I)或溴代烯烃(如
Figure BDA0002310809240000133
)在碱性条件(如碳酸钾丙酮溶液)中回流2-10h。
S212:使式(I-2)所示化合物和二卤代烷烃发生取代反应,生成式(II-1)所示化合物;
Figure BDA0002310809240000134
式(II-1)所示化合物中X表示卤素;
进一步地,步骤S212中二卤代烷烃为主链两端基被卤素取代的烷烃,如1,3-二溴丙烷;
进一步地,步骤S212的反应条件为碱性条件(如碳酸钾丙酮溶液)下回流3-8h。
S213:使式(II-1)所示化合物和NHR5R6反应,生成式(II-2)所示化合物;
Figure BDA0002310809240000141
进一步地,步骤S213的反应条件为:以DMF为溶剂,三乙胺为碱,在40℃-60℃的条件下反应20h-28h。
S214:使式(II-2)所示化合物和碘代烷基反应,生成式(II-3)所示化合物;
Figure BDA0002310809240000142
进一步地,步骤S214的反应条件为:以醇为溶剂,在10℃-40℃的条件下反应12h-36h。
在一实施例中,步骤S20包括以下步骤:
S221:使式(I-1)所示化合物和卤代烷烃或卤代烯烃发生取代反应,生成式(I-2)所示化合物;
Figure BDA0002310809240000143
进一步地,步骤S211为:使式(I-1)所示化合物和碘代烷烃(如C3H7I)或溴代烯烃(如
Figure BDA0002310809240000144
)在碱性条件(如碳酸钾丙酮溶液)中回流2-10h。
S222:使式(I-2)所示化合物和
Figure BDA0002310809240000145
反应,制得式(I-3)所示化合物;
Figure BDA0002310809240000146
其中,R3′和R4′各自独立地为H或
Figure BDA0002310809240000147
且R3′和R4′不同时为H;
进一步地,S222的反应条件为:碱性条件(如碳酸钾丙酮溶液)中回流4-12h。
S223:使式(I-3)所示化合物中的酯基水解,制得式(I-4)所示化合物;
Figure BDA0002310809240000148
其中,R5′和R6′各自独立地为H或
Figure BDA0002310809240000151
且R5′和R6′不同时为H。
步骤S223为酯水解反应,可以采用现有的反应条件在此不做特别限定。
进一步地,步骤S223的反应条件为:碱(如LiOH)的THF水溶液,在10℃-40℃的条件下反应1h-3h。
S224:使式(I-4)所示化合物和
Figure BDA0002310809240000152
反应,制得式(I-5)所示化合物;
Figure BDA0002310809240000153
其中,R7′和R8′各自独立地为H或
Figure BDA0002310809240000154
且R7′和R8′不同时为H。
步骤S224为酸和胺的缩合反应,可以采用现有的缩合反应条件,在此不做特别限定。
进一步地,S224的反应条件为:以HATU为缩合剂,DIPEA为碱,DMF为溶剂,在10℃-40℃的条件下反应12h-36h。
S225:使式(I-5)所示化合物中酯基水解,制得式(I-6)所示化合物;
Figure BDA0002310809240000155
其中,R9′和R10′各自独立地为H或
Figure BDA0002310809240000156
且R9′和R10′不同时为H。
步骤S225为酯水解反应,可以采用现有的反应条件在此不做特别限定。
进一步地,步骤S225的反应条件为:碱(如LiOH)的THF水溶液,在10℃-40℃的条件下反应1h-3h。
S226:使式(I-6)所示化合物和
Figure BDA0002310809240000157
反应,制得式(I-7)所示化合物;
Figure BDA0002310809240000158
R11′和R12′各自独立地为H或
Figure BDA0002310809240000159
且R11′和R12′不同时为H。
步骤S226为酸和胺的缩合反应,可以采用现有的缩合反应条件,在此不做特别限定。进一步地,S226的反应条件为:以HATU为缩合剂,DIPEA为碱,DMF为溶剂,在10℃-40℃的条件下反应12h-36h。
S227:使式(I-7)所示化合物中酯基水解,制得式(I-8)所示化合物;
Figure BDA0002310809240000161
其中,R13′和R14′各自独立地为H或
Figure BDA0002310809240000162
且R13′和R14′不同时为H。
步骤S227为酯水解反应,可以采用现有的反应条件在此不做特别限定。
进一步地,步骤S227的反应条件为:碱(如LiOH)的THF水溶液,在10℃-40℃的条件下反应1h-3h。
S228:使式(I-8)所示化合物和
Figure BDA0002310809240000163
反应,制得式(I-9)所示化合物;
Figure BDA0002310809240000164
其中,R15′和R16′各自独立地为H或
Figure BDA0002310809240000165
且R15′和R16′不同时为H。
步骤S228为酸和胺的缩合反应,可以采用现有的缩合反应条件,在此不做特别限定。进一步地,S228的反应条件为:以HATU为缩合剂,DIPEA为碱,DMF为溶剂,在10℃-40℃的条件下反应12h-36h。
需要说明的是,若上述步骤S221-S228中任一步骤获得了所需产物,则可以不再进行后续步骤,不应理解为对本发明的限制。
本发明还提供了上述黄酮类化合物在制备抗菌药物中的应用。
进一步地,抗菌药物为治疗革兰氏阳性细菌(包括耐甲氧西林金黄色葡萄球菌)介导疾病的药物。
下面列举具体实施例来对本发明进行说明。
化合物1的制备
将山奈酚(100mg,0.349mmol)溶于DMF(15mL)中,然后加入碳酸钾(120mg,0.873mmol)。将混合物在室温下搅拌0.5小时后,加入1-碘丙烷(70.4μL,0.722mmol),并于室温搅拌10小时。反应完成后,将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在真空条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯,3:1,v/v)纯化,得到化合物1为黄色固体(56.5mg,45%)。1H NMR(400MHz,CDCl3)δ12.62(s,1H),8.02(d,J=7.8Hz,2H),6.98(d,J=6.8Hz,2H),6.32(m,2H),3.98(t,J=6.6Hz,2H),3.91(t,J=6.7Hz,2H),1.89–1.79(m,2H),1.76–1.66(m,2H),1.04(t,J=7.5Hz,3H),0.91(t,J=7.4Hz,3H).13C NMR(100MHz,CDCl3)δ179.11,165.19,161.75,157.02,156.91(2×C),137.88,130.67(2×CH),122.46,115.76(2×CH),105.88,98.49,92.75,74.85,70.26,23.29,22.39,10.47,10.40.HRMS(ESI+):calculated for C21H23O6[M+H]+371.1495,found 371.1484.
化合物2的制备
以山奈酚(100mg,0.349mmol),碳酸钾(240mg,1.75mmol)和1-碘戊烷(95.6μL,0.73mmol)为起始原料,根据合成化合物1的方法,制备得到化合物2,为黄色固体(68.1mg,45%)。1H NMR(400MHz,CDCl3)δ12.63(s,1H),8.02(d,J=8.9Hz,2H),6.99(d,J=9.0Hz,2H),6.43(d,J=2.4Hz,1H),6.34(d,J=2.4Hz,1H),4.01(t,J=6.9Hz,2H),3.94(t,J=7.0Hz,2H),1.96–1.64(m,4H),1.61–1.08(m,8H),0.93(t,J=7.3Hz,3H),0.84(t,J=7.3Hz,3H).13C NMR(100MHz,CDCl3)δ178.99,165.05,161.72,158.60,156.80,156.69,137.87,130.54(2×CH),122.61,115.54(2×CH),105.81,98.32,92.61,73.17,68.69,29.62,28.61,28.03,27.93,22.37,22.36,13.96,13.93.HRMS(ESI+):calculated forC25H31O6[M+H]+427.2121,found 427.2111.
化合物3的制备
以山奈酚(200mg,0.699mmol),碳酸钾(289.7mg,2.1mmol)和1-碘庚烷(170.48μL,1.05mmol)为起始原料,根据合成化合物1的方法,制备得到化合物3,为棕黄色固体(88.6mg,26%)。1H NMR(400MHz,CDCl3)δ12.66(s,1H),8.15–7.91(m,2H),7.16–6.81(m,2H),6.43(d,J=1.6Hz,1H),6.34(d,J=1.8Hz,1H),3.99(dt,J=19.9,6.6Hz,4H),1.84–1.66(m,4H),1.39–1.20(m,16H),0.91–0.83(m,6H).13C NMR(100MHz,CDCl3)δ179.08,165.10,161.91,158.41,156.89,156.52,138.04,130.66,130.65,122.98,115.60,115.58,105.96,98.37,92.68,73.24,68.78,31.83,31.82,30.10,29.11,29.06,29.01,25.97,25.90,22.68,22.66,14.16,14.14.HRMS(ESI+):calculated for C29H39O6[M+H]+483.2747,found 483.2737.
化合物4的制备
以山奈酚(100mg,0.349mmol),碳酸钾(96.57mg,0.699mmol)和1-碘壬烷(112μL,0.629mmol)为起始原料,根据合成化合物1的方法,制备得到化合物4,为黄色固体(34.4mg,18%)。1H NMR(400MHz,CDCl3)δ12.67(s,1H),8.02(d,J=7.8Hz,2H),6.95(d,J=6.2Hz,2H),6.42(d,J=2.2Hz,1H),6.34(d,J=2.2Hz,1H),3.99(dt,J=16.3,6.7Hz,4H),1.87–1.61(m,6H),1.48–1.40(m,2H),1.35–1.23(m,20H),0.88(dt,J=4.7,3.5Hz,6H).13C NMR(100MHz,CDCl3)δ179.09,165.13,161.88,158.57,156.89,156.65,138.01,130.64(2×CH),122.82,115.60(2×CH),105.93,98.40,92.69,73.29,68.80,31.94(2×CH2),30.09,29.78,29.58,29.46,29.40,29.32(2×CH2),29.02,26.00,25.95,22.74(2×CH2),14.18(2×CH3).C33H47O6[M+H]+539.3373,found 539.3356.
化合物5的制备
将山奈酚(200mg,0.699mmol)溶于DMF(15mL)中,然后加入碳酸钾(483mg,3.49mmol)。将混合物在室温下搅拌0.5小时后,加入1-溴-3-甲基-2-丁烯(170μL,1.47mmol),并在65℃下搅拌1.5小时。反应完成后,将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在真空条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯,4:1,v/v)纯化,得到化合物5为浅黄色固体(142.9mg,50%)。1H NMR(400MHz,CDCl3)δ12.68(s,1H),8.03(d,J=9.1Hz,2H),6.98(d,J=9.2Hz,2H),6.45(d,J=2.4Hz,1H),6.36(d,J=2.4Hz,1H),5.63–5.21(m,2H),4.57(d,J=7.3Hz,2H),4.52(d,J=7.8Hz,2H),1.84–1.72(m,6H),1.67–1.54(m,6H).13C NMR(100MHz,CDCl3)δ179.23,164.90,161.71,159.08,157.48,156.88,139.69,139.41,137.27,130.69(2×CH),122.55,119.64,118.62,115.75(2×CH),105.84,98.65,92.99,69.27,65.58,25.90,25.83,18.36,18.03.HRMS(ESI+):calculatedfor C25H27O6[M+H]+423.1808,found 423.1797.
化合物6的制备
将化合物1(56.5mg,0.153mmol)溶于丙酮(10mL)中,然后加入碳酸钾(105.4mg,0.76mmol)和1,3-二溴丙烷(46.43μL,0.46mmol),将混合物回流4小时。反应完成后,将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在真空条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯,7:1,v/v)纯化,得到化合物6为黄色固体(35.1mg,47%)。1H NMR(400MHz,CDCl3)δ12.67(s,1H),8.07(d,J=9.2Hz,2H),7.01(d,J=9.3Hz,2H),6.42(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.20(t,J=6.0Hz,2H),3.96(dt,J=11.8,6.8Hz,4H),3.63(t,J=6.5Hz,2H),2.46–2.25(m,2H),1.88–1.61(m,4H),1.04(t,J=7.5Hz,3H),0.95(t,J=7.5Hz,3H).13C NMR(100MHz,CDCl3)δ178.99,165.02,162.03,160.71,156.84,156.05,138.13,130.40(2×CH),123.36,114.42(2×CH),106.00,98.27,92.60,74.59,70.19,65.52,32.28,29.87,23.43,22.41,10.50,10.48.HRMS(APCI+):calculated forC24H28BrO6[M+H]+491.1069,found 491.1055.
化合物7的制备
以化合物2(61.2mg,0.143mmol),碳酸钾(59.5mg,0.43mmol)和1,3-二溴丙烷(43.8μL,0.43mmol)为起始原料,根据合成化合物6的方法,制备得到化合物7,为黄色固体(40.5mg,56%)。1H NMR(400MHz,CDCl3)δ12.67(s,1H),8.06(d,J=8.8Hz,2H),7.01(d,J=8.9Hz,2H),6.42(d,J=2.1Hz,1H),6.33(d,J=2.1Hz,1H),4.20(t,J=5.8Hz,2H),3.99(dt,J=13.4,6.7Hz,4H),3.63(t,J=6.4Hz,2H),2.43–2.31(m,2H),1.85–1.76(m,2H),1.76–1.67(m,2H),1.45–1.27(m,8H),0.94(t,J=7.1Hz,3H),0.87(t,J=7.1Hz,3H).13CNMR(100MHz,CDCl3)δ178.99,165.01,162.03,160.71,156.84,156.06,138.15,130.39(2×CH),123.37,114.41(2×CH),105.99,98.26,92.60,73.06,68.73,65.52,32.27,29.86,29.85,28.73,28.16,28.11,22.51,22.48,14.10,14.08.HRMS(APCI+):calculated forC28H36BrO6[M+H]+547.1695,found 547.1679.
化合物8的制备
以化合物3(88.6mg,0.184mmol),碳酸钾(63.4mg,0.46mmol)和1,3-二溴丙烷(139.8μL,1.38mmol)为起始原料,根据合成化合物6的方法,制备得到化合物8,为黄色固体(79.1mg,72%)。1H NMR(400MHz,CDCl3)δ12.68(s,1H),8.06(d,J=9.0Hz,2H),7.01(d,J=9.0Hz,2H),6.42(d,J=2.2Hz,1H),6.33(d,J=2.2Hz,1H),4.20(t,J=5.8Hz,2H),4.00(dt,J=12.1,6.7Hz,4H),3.63(t,J=6.4Hz,2H),2.37(p,J=6.1Hz,2H),1.85–1.75(m,2H),1.75–1.66(m,2H),1.48–1.24(m,16H),0.91–0.83(m,6H).13C NMR(100MHz,CDCl3)δ178.99,165.02,162.04,160.70,156.85,156.07,138.16,130.41(2×CH),123.39,114.40(2×CH),106.00,98.26,92.60,73.10,68.74,65.51,32.28,31.87,31.82,30.17,29.85,29.12,29.07,29.04,25.97,25.95,22.68,22.67,14.18,14.16.HRMS(APCI+):calculatedfor C32H44BrO6[M+H]+603.2321,found 603.2307.
化合物9的制备
以化合物4(98mg,0.182mmol),碳酸钾(62.9mg,0.45mmol)和1,3-二溴丙烷(138.4μL,1.36mmol)为起始原料,根据合成化合物6的方法,制备得到化合物9,为黄色固体(69.5mg,58%)。1H NMR(400MHz,CDCl3)δ12.68(s,1H),8.07(d,J=9.0Hz,2H),7.01(d,J=9.0Hz,2H),6.42(d,J=2.2Hz,1H),6.33(d,J=2.1Hz,1H),4.20(t,J=5.8Hz,2H),4.00(dt,J=11.6,6.6Hz,4H),3.63(t,J=6.4Hz,2H),2.37(p,J=6.1Hz,2H),1.84–1.65(m,4H),1.46–1.24(m,24H),0.87(dt,J=4.8,3.4Hz,6H).13C NMR(100MHz,CDCl3)δ178.88,164.91,161.93,160.59,156.74,155.94,138.05,130.30(2×CH),123.29,114.29(2×CH),105.89,98.15,92.50,72.99,68.64,65.40,32.17,31.85,31.83,30.06,29.72,29.50,29.47,29.35,29.29,29.21(2×CH2),28.92,25.90,25.88,22.64(2×CH2),14.09,14.07.HRMS(APCI+):calculated for C36H52BrO6[M+H]+659.2947,found 659.2933.
化合物10的制备
以化合物5(30mg,0.071mmol),碳酸钾(25.1mg,0.18mmol)和1,3-二溴丙烷(54μL,0.53mmol)为起始原料,根据合成化合物6的方法,制备得到化合物10,为棕黄色固体的产物(29.3mg,76%)。1H NMR(400MHz,CDCl3)δ12.77–12.67(m,1H),8.22–7.96(m,2H),7.13–6.87(m,2H),6.54–6.40(m,1H),6.38–6.27(m,1H),5.61–5.26(m,2H),4.71–4.43(m,4H),4.19(t,J=6.3Hz,2H),3.78–3.48(m,2H),2.52–2.27(m,2H),1.92–1.72(m,6H),1.68(s,3H),1.62(s,3H).13C NMR(100MHz,CDCl3)δ178.91,164.54,161.86,160.49,156.63,156.17,139.36,139.11,137.42,130.27(2×CH),123.37,119.70,118.57,114.24(2×CH),105.81,98.24,92.65,68.82,65.36,65.33,32.11,29.74,25.76,25.71,18.20,17.95.HRMS(APCI+):calculated for C28H32BrO6[M+H]+543.1382,found 543.1363.
化合物11的制备
将化合物6(47.8mg,0.097mmol)溶于DMF(4mL)溶液中,然后加入二乙胺(1mL),将混合物在50℃下搅拌24小时。反应完成后,将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在真空条件下浓缩。粗产物通过硅胶色谱法(乙酸乙酯/乙醇/三乙胺,1/1/0.1,v/v/v)纯化,得到化合物11为黄色凝胶(27.1mg,58%)。1H NMR(400MHz,CD3OD)δ8.04–7.95(m,2H),7.02–6.93(m,2H),6.49–6.40(m,1H),6.26–6.19(m,1H),4.11–4.03(m,2H),4.00–3.94(m,2H),3.90–3.83(m,2H),2.73–2.67(m,2H),2.62(q,J=7.2Hz,4H),2.02–1.94(m,2H),1.84–1.66(m,4H),1.10–1.02(m,9H),0.94(t,J=7.4Hz,3H).13C NMR(100MHz,CD3OD)δ180.13,166.59,162.83,162.63,158.19,157.70,139.05,131.47,131.44,123.97,115.44(2×CH),106.76,99.25,93.51,75.52,71.35,67.53,50.35,47.90(2×CH2),27.06,24.39,23.49,11.42(2×CH3),10.94,10.82.HRMS(ESI+):calculated for C28H38NO6[M+H]+484.2699,found 484.2676.
化合物12的制备
以化合物7(50mg,0.091mmol)和二乙胺(1mL)为起始原料,根据合成化合物11的方法,制备得到化合物12,为棕黄色固体(31.4mg,64%)。1H NMR(400MHz,CD3OD)δ7.96(d,J=8.5Hz,2H),6.96(d,J=8.5Hz,2H),6.41(s,1H),6.19(d,J=1.9Hz,1H),4.06(t,J=5.9Hz,2H),3.97(t,J=6.3Hz,2H),3.89(t,J=6.6Hz,2H),2.73–2.66(m,2H),2.61(q,J=7.2Hz,4H),2.02–1.92(m,2H),1.80–1.63(m,4H),1.48–1.29(m,8H),1.08(t,J=7.2Hz,6H),0.96(t,J=7.0Hz,3H),0.88(t,J=7.1Hz,3H).13C NMR(100MHz,CD3OD)δ180.00,166.43,162.75,162.53,158.04,157.50,139.01,131.41(2×CH),123.92,115.35(2×CH),106.71,99.19,93.43,73.79,69.83,67.53,50.34,47.88(2×CH2),30.85,29.92,29.31(2×CH2),27.09,23.60,23.53,14.49(2×CH3),11.47(2×CH3).HRMS(ESI+):calculated forC32H46NO6[M+H]+540.3325,found 540.3301.
化合物13的制备
以化合物8(63.8mg,0.106mmol)和二乙胺(1mL)为起始原料,根据合成化合物11的方法,制备得到化合物13,为黄色凝胶(34.6mg,56%)。1H NMR(400MHz,CD3OD)δ7.98(d,J=8.8Hz,2H),6.99(d,J=8.9Hz,2H),6.45(d,J=2.0Hz,1H),6.22(d,J=2.1Hz,1H),4.08(t,J=6.0Hz,2H),3.99(t,J=6.4Hz,2H),3.91(t,J=6.5Hz,2H),2.80–2.72(m,2H),2.67(q,J=7.2Hz,4H),2.05–1.95(m,2H),1.76(dd,J=14.4,6.7Hz,2H),1.69–1.61(m,2H),1.46(dd,J=10.2,5.0Hz,2H),1.38–1.30(m,8H),1.29–1.24(m,6H),1.11(t,J=7.2Hz,6H),0.93–0.86(m,6H).13C NMR(100MHz,CD3OD)δ180.05,166.49,162.77,162.51,158.12,157.66,139.02,131.47(2×CH),123.99,115.36(2×CH),106.72,99.20,93.45,73.85,69.84,67.42,50.32,47.90(2×CH2),33.03,33.01,31.10(2×CH2),30.26,30.18,27.09,27.08,26.93,23.73,23.71,14.53,14.49,11.28(2×CH3).HRMS(ESI+):calculated forC36H54NO6[M+H]+596.3951,found 596.3923.
化合物14的制备
以化合物9(51.8mg,0.079mmol)和二乙胺(1mL)为起始原料,根据合成化合物11的方法,制备得到化合物14,为黄色凝胶(40.2mg,79%)。1H NMR(400MHz,CDCl3)δ8.05(d,J=9.3Hz,2H),6.99(d,J=9.3Hz,2H),6.41(d,J=2.3Hz,1H),6.32(d,J=2.3Hz,1H),4.32–3.82(m,6H),3.51–3.14(m,2H),2.68–2.55(m,4H),2.36(br,2H),2.05–1.92(m,2H),1.90–1.16(m,26H),1.05(t,J=7.2Hz,6H),0.91–0.79(m,6H).13C NMR(100MHz,CDCl3)δ178.99,164.99,162.02,161.13,156.85,156.26,138.08,130.34(2×CH),122.97,114.41(2×CH),105.99,98.25,92.60,73.08,68.74,66.55,59.17,49.32,47.01,31.95,31.93,30.15,29.60,29.57,29.45,29.39,29.31,29.02,26.85,26.00,25.98,22.74(2×CH2),14.19,14.17,11.64(2×CH3).HRMS(ESI+):calculated for C40H62NO6[M+H]+652.4577,found652.4547.
化合物15的制备
以化合物10(94.1mg,0.173mmol)和二乙胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物15,为黄色凝胶(90.8mg,97%)。1H NMR(400MHz,CD3OD)δ8.09–7.94(m,2H),7.04–6.89(m,2H),6.51–6.38(m,1H),6.29–6.17(m,1H),5.50–5.28(m,2H),4.61–4.52(m,2H),4.47(d,J=6.3Hz,2H),4.11–4.00(m,2H),2.74–2.66(m,2H),2.62(q,J=7.2Hz,4H),2.07–1.92(m,2H),1.79(s,3H),1.76(s,3H),1.65(s,3H),1.56(s,3H),1.09(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ179.93,165.97,162.46,162.24,157.75,157.59,140.08,139.25,138.12,131.20(2×CH),123.81,120.80,120.07,115.09(2×CH),106.38,99.12,93.49,69.55,67.26,66.37,50.07,47.62(2×CH2),26.81,25.77,25.75,18.19,17.96,11.23(2×CH3).HRMS(ESI+):calculated for C30H38NO6[M+H]+536.3012,found536.2986.
化合物16的制备
以化合物5(33mg,0.078mmol),碳酸钾(26.9mg,0.195mmol)和1,2-二溴乙烷(50.5μL,0.586mmol)为起始原料,根据合成化合物10的方法,制备得到化合物16,为黄色固体(22.8mg,55%)。1H NMR(400MHz,CDCl3)δ12.69(s,1H),8.08(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),6.38(d,J=35.1Hz,2H),5.48(t,J=6.2Hz,1H),5.38(t,J=7.1Hz,1H),4.56(d,J=7.0Hz,4H),4.37(t,J=6.0Hz,2H),3.67(t,J=5.9Hz,2H),1.81(s,3H),1.76(s,3H),1.68(s,3H),1.62(s,3H).13C NMR(100MHz,CDCl3)δ178.87,164.55,161.81,159.80,156.58,155.93,139.34,139.04,137.45,130.28(2×CH),123.79,119.65,118.55,114.33(2×CH),105.77,98.24,92.62,68.81,67.74,65.32,28.69,25.72,25.67,18.17,17.91.HRMS(APCI+):calculated for C27H30BrO6[M+H]+529.1226,found 529.1208.
化合物17的制备
以化合物5(40mg,0.095mmol),碳酸钾(32.7mg,0.24mmol)和1,4-二溴丁烷(79.2μL,0.66mmol)为起始原料,根据合成化合物10的方法,制备得到化合物17,为黄色固体(44.8mg,85%)。1H NMR(400MHz,CDCl3)δ12.72(s,1H),8.08(d,J=9.2Hz,2H),6.98(d,J=9.3Hz,2H),6.44(d,J=2.4Hz,1H),6.35(d,J=2.4Hz,1H),5.60–5.27(m,2H),4.67–4.47(m,4H),4.08(t,J=6.2Hz,2H),3.51(t,J=6.7Hz,2H),2.25–1.92(m,4H),1.85–1.56(m,12H).13C NMR(100MHz,CDCl3)δ179.07,164.70,162.02,160.85,156.79,156.40,139.48,139.25,137.54,130.41(2×CH),123.34,119.87,118.73,114.35(2×CH),105.97,98.39,92.81,68.97,67.11,65.49,33.41,29.48,27.88,25.91,25.86,18.35,18.10.HRMS(APCI+):calculated for C29H34BrO6[M+H]+557.1539,found 557.1521.
化合物18的制备
以化合物5(78.1mg,0.185mmol),碳酸钾(63.9mg,0.46mmol)和1,5-二溴戊烷(188μL,1.39mmol)为起始原料,根据合成化合物10的方法,制备得到化合物18,为棕黄色固体(86.6mg,82%)。1H NMR(400MHz,CDCl3)δ12.72(s,1H),8.07(d,J=8.2Hz,2H),6.97(d,J=8.3Hz,2H),6.42(d,J=8.2Hz,1H),6.33(d,J=10.4Hz,1H),5.48(t,J=6.2Hz,1H),5.40(t,J=7.0Hz,1H),4.63–4.50(m,4H),4.05(t,J=6.2Hz,2H),3.45(t,J=6.6Hz,2H),2.05–1.62(m,18H).13C NMR(100MHz,CDCl3)δ179.09,164.69,162.03,160.98,156.80,156.48,139.49,139.28,137.53,130.41(2×CH),123.23,119.87,118.72,114.38(2×CH),105.98,98.38,92.83,68.98,67.83,65.49,33.61,32.52,28.42,25.91,25.86,24.88,18.35,18.10.HRMS(APCI+):calculated for C30H36BrO6[M+H]+571.1695,found 571.1682.
化合物19的制备
以化合物5(81.8mg,0.194mmol),碳酸钾(66.9mg,0.48mmol)和1,6-二溴己烷(224μL,1.45mmol)为起始原料,根据合成化合物10的方法,制备得到化合物19,为黄色固体(88.4mg,78%)。1H NMR(400MHz,CDCl3)δ12.72(s,1H),8.07(d,J=8.2Hz,2H),6.97(d,J=8.3Hz,2H),6.42(d,J=8.4Hz,1H),6.33(d,J=9.8Hz,1H),5.48(t,J=6.3Hz,1H),5.40(t,J=7.1Hz,1H),4.62–4.49(m,4H),4.04(t,J=6.2Hz,2H),3.43(t,J=6.7Hz,2H),1.95–1.80(m,7H),1.76(s,3H),1.68(s,3H),1.62(s,3H),1.56–1.44(m,4H).13C NMR(100MHz,CDCl3)δ178.90,164.51,161.84,160.91,156.62,156.33,139.30,139.07,137.33,130.22(2×CH),122.95,119.72,118.58,114.21(2×CH),105.79,98.22,92.63,68.79,67.81,65.32,33.69,32.56,28.90,27.82,25.75,25.70,25.19,18.19,17.94.HRMS(APCI+):calculated for C31H38BrO6[M+H]+585.1582,found 585.1534.
化合物20的制备
以化合物5(76.6mg,0.18mmol),碳酸钾(62.6mg,0.45mmol)和1,8-二溴辛烷(250.5μL,1.36mmol)为起始原料,根据合成化合物10的方法,制备得到化合物20,为橙色油状物(92.9mg,83%)。1H NMR(400MHz,CDCl3)δ12.73(s,1H),8.07(d,J=8.1Hz,2H),6.97(d,J=8.2Hz,2H),6.46–6.30(m,2H),5.48(t,J=6.2Hz,1H),5.40(t,J=7.2Hz,1H),4.61–4.50(m,4H),4.03(t,J=6.3Hz,2H),3.41(t,J=6.7Hz,2H),1.91–1.62(m,16H),1.51–1.33(m,8H).13C NMR(100MHz,CDCl3)δ178.99,164.60,161.94,161.08,156.72,156.45,139.37,139.14,137.42,130.30(2×CH),122.98,119.83,118.68,114.32(2×CH),105.89,98.31,92.72,68.88,68.10,65.41,33.98,32.77,29.19,29.13,28.69,28.09,25.94,25.84,25.79,18.28,18.03.HRMS(APCI+):calculated for C33H42BrO6[M+H]+613.2165,found613.2141.
化合物21的制备
以化合物5(73mg,0.173mmol),碳酸钾(60.5mg,0.44mmol)和1,10-二溴癸烷(293μL,1.3mmol)为起始原料,根据合成化合物10的方法,制备得到化合物21,为棕色油状物(75.4mg,68%)。1H NMR(400MHz,CDCl3)δ12.73(s,1H),8.07(d,J=9.3Hz,2H),6.98(d,J=9.3Hz,2H),6.44(d,J=2.4Hz,1H),6.35(d,J=2.3Hz,1H),5.69–5.24(m,2H),4.69–4.44(m,4H),4.03(t,J=6.8Hz,2H),3.41(t,J=7.0Hz,2H),2.02–1.03(m,28H).13C NMR(100MHz,CDCl3)δ179.09,164.68,162.04,161.18,156.81,156.56,139.47,139.28,137.50,130.39(2×CH),123.06,119.88,118.73,114.40(2×CH),105.98,98.37,92.83,68.97,68.24,65.48,34.12,32.88,29.51,29.43,29.40,29.23,28.81,28.23,26.07,25.91,25.85,18.35,18.09.HRMS(APCI+):calculated for C35H46BrO6[M+H]+641.2478,found 641.2456.
化合物22的制备
以化合物16(47.7mg,0.090mmol)和二乙胺(0.5mL)为起始原料,根据合成化合物11的方法,制备得到化合物22,为棕色凝胶(28.5mg,61%)。1H NMR(400MHz,CD3OD)δ8.06(d,J=7.4Hz,2H),7.11–6.97(m,2H),6.51(d,J=7.7Hz,1H),6.26(d,J=6.2Hz,1H),5.52–5.41(m,1H),5.37–5.28(m,1H),4.64–4.56(m,2H),4.53–4.47(m,2H),4.23(d,J=2.9Hz,2H),3.15–3.04(m,2H),2.87–2.78(m,4H),1.80(s,3H),1.77(s,3H),1.64(s,3H),1.56(s,3H),1.18(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ180.23,166.30,162.71,161.92,158.07,157.84,140.45,139.59,138.40,131.53(2×CH),124.55,120.93,120.23,115.43(2×CH),106.62,99.39,93.75,69.79,66.61,66.20,52.36,49.66(2×CH2),25.94,25.92,18.35,18.11,10.92(2×CH3).HRMS(ESI+):calculated for C31H40NO6[M+H]+522.2856,found 522.2828.
化合物23的制备
以化合物17(46.3mg,0.083mmol)和二乙胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物23,为橙色固体(42.2mg,92%)。1H NMR(400MHz,CD3OD)δ8.03(d,J=4.6Hz,2H),7.05–6.94(m,2H),6.56–6.45(m,1H),6.26(d,J=7.6Hz,1H),5.49–5.30(m,2H),4.66–4.54(m,2H),4.49(d,J=7.3Hz,2H),4.07(d,J=5.9Hz,2H),2.66–2.52(m,6H),1.85–1.67(m,10H),1.65(s,3H),1.56(s,3H),1.07(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ180.13,166.18,162.72,162.53,157.97,157.82,140.26,139.43,138.32,131.41(2×CH),123.95,121.02,120.29,115.31(2×CH),106.60,99.33,93.68,69.75,68.95,66.58,58.31,53.41,47.68,28.39,25.98,25.95,23.76,18.39,18.17,11.34(2×CH3).HRMS(ESI+):calculated for C33H44NO6[M+H]+550.3169,found 550.3141.
化合物24的制备
以化合物18(29.8mg,0.052mmol)和二乙胺(0.5mL)为起始原料,根据合成化合物11的方法,制备得到化合物24,为橙色凝胶(27mg,91%)。1H NMR(400MHz,CD3OD)δ8.00(d,J=6.7Hz,2H),7.01–6.93(m,2H),6.47(d,J=10.8Hz,1H),6.24(d,J=7.4Hz,1H),5.49–5.31(m,2H),4.60–4.46(m,4H),4.03(d,J=6.1Hz,2H),2.66–2.57(m,4H),2.56–2.51(m,2H),1.88–1.71(m,8H),1.65(s,3H),1.58–1.52(m,5H),1.28–1.25(m,2H),1.09–1.03(m,6H).13C NMR(100MHz,CD3OD)δ180.25,166.30,162.78,162.69,158.09,158.03,140.39,139.56,138.35,131.49(2×CH),123.99,121.03,120.31,115.38(2×CH),106.65,99.41,93.77,69.80,69.11,66.64,53.70,47.77(2×CH2),30.23,26.86,26.00,25.97,25.29,18.40,18.18,11.16(2×CH3).HRMS(ESI+):calculated for C34H46NO6[M+H]+564.3325,found 564.3299.
化合物25的制备
以化合物19(55.9mg,0.095mmol)和二乙胺(1mL)为起始原料,根据合成化合物11的方法,制备得到化合物25,为黄色凝胶(22.6mg,41%)。1H NMR(400MHz,CD3OD)δ7.98(d,J=8.7Hz,2H),6.93(d,J=8.8Hz,2H),6.44(d,J=15.7Hz,1H),6.22(d,J=9.7Hz,1H),5.47–5.28(m,2H),4.61–4.52(m,2H),4.47(d,J=6.5Hz,2H),4.08–3.91(m,2H),2.64–2.54(m,4H),2.53–2.46(m,2H),1.82–1.72(m,8H),1.65(s,3H),1.57(s,3H),1.39–1.25(m,6H),1.08–1.03(m,6H).13C NMR(100MHz,CD3OD)δ180.24,166.29,162.76,162.70,158.08,158.07,140.40,139.56,138.30,131.46(2×CH),123.94,120.97,120.26,115.36(2×CH),106.62,99.38,93.74,69.77,69.12,66.60,53.66,47.71(2×CH2),30.25,28.50,27.07,26.96,25.95,25.92,18.35,18.12,11.11(2×CH3).HRMS(ESI+):calculated for C35H48NO6[M+H]+578.3482,found 578.3454.
化合物26的制备
以化合物20(37.8mg,0.062mmol)和二乙胺(2mL)为起始原料,根据合成化合物11的方法,所得粗产物通过RP-HPLC纯化,制备得到化合物26,为黄色油状物(35.5mg,95%)。1H NMR(400MHz,CD3OD)δ8.04(d,J=9.0Hz,2H),6.99(d,J=9.1Hz,2H),6.51(d,J=2.2Hz,1H),6.27(d,J=2.2Hz,1H),5.51–5.43(m,1H),5.39–5.30(m,1H),4.60(d,J=6.6Hz,2H),4.50(d,J=7.5Hz,2H),4.04(t,J=6.4Hz,2H),2.59(q,J=7.2Hz,4H),2.51–2.44(m,2H),1.84–1.71(m,8H),1.65(s,3H),1.57(s,3H),1.54–1.45(m,4H),1.43–1.32(m,6H),1.06(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ180.28,166.38,162.68,161.83,158.14,157.89,140.58,139.75,138.38,131.57(2×CH),124.70,120.84,120.15,115.39(2×CH),106.63,99.45,93.78,69.78,66.63(2×CH2),65.78,62.85,59.90,25.92(2×CH2),25.90(2×CH2),25.16(2×CH3),23.49,20.73,18.32,18.07,13.99(2×CH3).HRMS(ESI+):calculated forC37H52NO6[M+H]+606.3795,found 606.3765.
化合物27的制备
以化合物21(36mg,0.056mmol)和二丁胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物27,为黄色固体(11.2mg,35%)。1H NMR(400MHz,CDCl3)δ12.72(s,1H),8.07(s,1H),8.05(s,1H),6.97(d,J=8.9Hz,2H),6.43(d,J=2.2Hz,1H),6.34(d,J=2.2Hz,1H),5.47(t,J=6.5Hz,1H),5.38(t,J=7.3Hz,1H),4.55(t,J=7.4Hz,4H),4.02(t,J=6.6Hz,2H),2.58(q,J=7.1Hz,4H),2.50–2.40(m,2H),2.06–1.89(m,4H),1.83–1.78(m,5H),1.75(s,3H),1.67(s,3H),1.61(s,3H),1.49–1.41(m,4H),1.30–1.28(m,6H),1.04(t,J=7.2Hz,6H).13C NMR(100MHz,CDCl3)δ179.09,164.68,162.05,161.20,156.81,156.58,139.47,139.27,137.50,130.38(2×CH),123.06,119.88,118.73,114.41(2×CH),105.99,98.37,92.83,68.97,68.27,65.48,46.78(3×CH3),29.77,29.63,29.60,29.58,29.44,29.24,27.71,26.08,25.90,25.84,18.35,18.09,11.26,11.25.HRMS(ESI+):calculatedfor C39H56NO6[M+H]+634.4108,found 634.4116.
化合物28的制备
以化合物10(99.6mg,0.183mmol)和二甲胺(1mL)为起始原料,根据合成化合物11的方法,制备得到化合物28,为黄色固体(79.6mg,86%)。1H NMR(400MHz,CDCl3)δ12.73(s,1H),8.07(d,J=9.1Hz,2H),6.99(d,J=9.3Hz,2H),6.44(d,J=2.5Hz,1H),6.35(d,J=2.5Hz,1H),5.62–5.30(m,2H),4.65–4.48(m,4H),4.15–4.03(m,2H),2.47(t,2H),2.27(s,6H),2.07–1.92(m,2H),1.85–1.80(m,3H),1.77–1.74(m,3H),1.70–1.64(m,3H),1.63–1.59(m,3H).13C NMR(100MHz,CDCl3)δ179.08,164.68,162.02,161.06,156.80,156.52,139.47,139.26,137.51,130.37(2×CH),123.16,119.87,118.73,114.42(2×CH),105.98,98.39,92.81,68.97,66.45,65.48,56.34,45.59(2×CH3),27.51,25.90,25.84,18.35,18.09.HRMS(ESI+):calculated for C30H38NO6[M+H]+508.2699,found 508.2693.
化合物29的制备
以化合物10(45mg,0.083mmol)和二丙胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物29,为黄色固体(29.9mg,65%)。1H NMR(400MHz,CDCl3)δ8.08(d,J=9.1Hz,2H),7.05(d,J=9.1Hz,2H),6.56(s,1H),6.30(d,J=2.1Hz,1H),5.54–5.42(m,1H),5.35–5.28(m,1H),4.62(d,J=6.3Hz,2H),4.52(d,J=7.5Hz,2H),4.15(t,J=6.0Hz,2H),2.97–2.86(m,2H),2.76–2.65(m,4H),2.11–2.02(m,2H),1.81(s,3H),1.78(s,3H),1.65–1.56(m,10H),0.96(t,J=7.4Hz,6H).13C NMR(100MHz,CDCl3)δ179.08,164.69,162.02,160.99,156.80,156.51,139.49,139.26,137.51,130.39(2×CH),123.21,119.86,118.72,114.38(2×CH),105.97,98.38,92.81,68.96,66.29,65.48,56.01(2×CH2),50.57,26.62,25.90,25.84,19.77(2×CH2),18.34,18.08,11.91(2×CH3).HRMS(ESI+):calculated forC34H46NO6[M+H]+564.3325,found 564.3298.
化合物30的制备
以化合物10(48.1mg,0.089mmol)和二丁胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物30,为黄色固体(42.8mg,82%)。1H NMR(400MHz,CD3OD)δ8.01(d,J=9.0Hz,2H),6.96(d,J=9.0Hz,2H),6.46(d,J=2.2Hz,1H),6.23(d,J=2.2Hz,1H),5.49–5.41(m,1H),5.37–5.30(m,1H),4.57(d,J=6.6Hz,2H),4.48(d,J=7.4Hz,2H),4.06(t,J=6.1Hz,2H),2.70–2.62(m,2H),2.52–2.44(m,4H),2.02–1.91(m,2H),1.80(s,3H),1.76(s,3H),1.65(s,3H),1.57(s,3H),1.50–1.43(m,4H),1.36–1.29(m,4H),0.93(t,J=7.3Hz,6H).13C NMR(100MHz,CD3OD)δ180.28,166.33,162.75,162.59,158.13(2×C),140.48,139.63,138.30,131.49(2×CH),124.07,120.92,120.22,115.38(2×CH),106.62,99.40,93.76,69.77,67.38,66.60,54.95(2×CH2),51.45,29.83(2×CH2),27.33,25.94,25.91,21.82(2×CH2),18.33,18.10,14.44(2×CH3).HRMS(ESI+):calculated for C36H50NO6[M+H]+592.3638,found 592.3609.
化合物31的制备
以化合物10(64.2mg,0.118mmol)和四氢吡咯(1.5mL)为起始原料,根据合成化合物11的方法,制备得到化合物31,为黄色固体(33mg,50%)。1H NMR(400MHz,CD3OD)δ7.97(d,J=9.1Hz,2H),6.93(d,J=9.1Hz,2H),6.41(d,J=2.1Hz,1H),6.19(d,J=2.1Hz,1H),5.51–5.39(m,1H),5.39–5.27(m,1H),4.54(d,J=6.6Hz,2H),4.46(d,J=7.4Hz,2H),4.06(t,J=6.1Hz,2H),2.80–2.74(m,2H),2.73–2.67(m,4H),2.10–1.98(m,2H),1.95–1.83(m,4H),1.79(s,3H),1.75(s,3H),1.65(s,3H),1.56(s,3H).13C NMR(100MHz,CD3OD)δ180.43,166.49,162.89,162.57,158.27,158.22,140.66,139.80,138.47,131.65(2×CH),124.38,121.04,120.35,115.52(2×CH),106.76,99.55,93.91,69.92,67.34,66.75,55.28(2×CH2),54.27,29.13,26.07,26.05,24.32(2×CH2),18.47,18.22.HRMS(ESI+):calculatedfor C32H40NO6[M+H]+534.2856,found 534.2851.
化合物32的制备
以化合物10(50mg,0.092mmol)和1-甲基哌嗪(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物32,为黄色固体(44.9mg,86%)。1H NMR(400MHz,CD3OD)δ7.97(d,J=8.4Hz,2H),6.93(d,J=8.4Hz,2H),6.40(s,1H),6.19(s,1H),5.43(t,J=6.0Hz,1H),5.33(t,J=7.2Hz,1H),4.54(d,J=6.5Hz,2H),4.46(d,J=7.3Hz,2H),4.06(t,J=6.0Hz,2H),2.97–2.52(m,10H),2.49(s,3H),2.07–1.96(m,2H),1.79(s,3H),1.75(s,3H),1.65(s,3H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.15,166.20,162.64,162.43,157.98,157.84,140.34,139.52,138.30,131.41(2×CH),124.05,120.96,120.24,115.32(2×CH),106.57,99.35,93.70,69.75,67.14,66.59,55.70,55.16(2×CH2),52.84(2×CH2),45.15,27.29,25.96,25.94,18.38,18.15.HRMS(ESI+):calculated for C33H43N2O6[M+H]+563.3121,found 563.3114.
化合物33的制备
以化合物10(50mg,0.092mmol)和硫代吗啉(2mL)为起始原料,根据合成化合物11的方法,所得粗产物通过RP-HPLC纯化,制备得到化合物33,为黄色凝胶(37.8mg,75%)。1HNMR(400MHz,CD3OD)δ8.02(d,J=30.9Hz,2H),7.09–6.95(m,2H),6.59–6.46(m,1H),6.28(d,J=2.8Hz,1H),5.51–5.43(m,1H),5.33(t,J=7.1Hz,1H),4.60(s,2H),4.51(d,J=7.1Hz,2H),4.14(s,2H),3.16–3.05(m,4H),3.00–2.89(m,2H),2.86–2.80(m,4H),2.13(br,2H),1.81(s,3H),1.78(s,3H),1.65(s,3H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.36,166.44,162.79,162.34,158.22(2×C),140.65,139.78,138.32,131.57(2×CH),124.42,120.84,120.17,115.42(2×CH),106.63,99.44,93.82,69.78,66.89,66.62,56.69,55.87(2×CH2),27.31(2×CH2),26.15,25.91,25.88,18.29,18.03.HRMS(ESI+):calculated forC32H40NO6S[M+H]+566.2576,found 566.2568.
化合物34的制备
以化合物10(46.4mg,0.085mmol)和吗啉(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物34,为橙色固体(31.1mg,70%)。1H NMR(400MHz,CD3OD)δ8.05(d,J=9.1Hz,2H),7.01(d,J=9.1Hz,2H),6.53(d,J=2.2Hz,1H),6.28(d,J=2.2Hz,1H),5.52–5.42(m,1H),5.39–5.28(m,1H),4.60(d,J=6.6Hz,2H),4.51(d,J=7.5Hz,2H),4.12(t,J=6.2Hz,2H),3.75–3.68(m,4H),2.61–2.45(m,6H),2.08–1.97(m,2H),1.81(s,3H),1.78(s,3H),1.65(s,3H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.18,166.22,162.69,162.49,158.00,157.87,140.34,139.52,138.33,131.42(2×CH),124.05,120.99,120.27,115.33(2×CH),106.60,99.35,93.73,69.76,67.67(2×CH2),67.33,66.59,56.65,54.80(2×CH2),27.16,25.96,25.93,18.37,18.15.HRMS(ESI+):calculated for C32H40NO7[M+H]+550.2805,found 550.2796.
化合物35的制备
以化合物10(42.1mg,0.077mmol)和正丙胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物35,为黄色固体(31mg,75%)。1H NMR(400MHz,CD3OD)δ8.03(d,J=8.8Hz,2H),6.99(d,J=8.9Hz,2H),6.50(d,J=1.8Hz,1H),6.25(d,J=2.1Hz,1H),5.44(t,J=6.2Hz,1H),5.30(t,J=7.5Hz,1H),4.57(d,J=6.2Hz,2H),4.48(d,J=7.5Hz,2H),4.10(t,J=5.7Hz,2H),2.79(t,J=7.3Hz,2H),2.61–2.53(m,2H),2.06–1.95(m,2H),1.78(s,3H),1.75(s,3H),1.62(s,3H),1.57–1.50(m,5H),0.93(t,J=7.4Hz,3H).13C NMR(100MHz,CD3OD)δ180.15,166.20,162.68,162.41,157.98,157.82,140.32,139.49,138.32,131.42(2×CH),124.08,120.97,120.26,115.30(2×CH),106.58,99.33,93.70,69.76,67.56,66.58,52.56,47.60,29.91,25.95,25.93,23.37,18.37,18.14,12.06.HRMS(ESI+):calculated for C31H40NO6[M+H]+522.2856,found 522.2849.
化合物36的制备
以化合物10(49.8mg,0.092mmol)和正戊胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物36,为棕黄色固体(35.4mg,71%)。1H NMR(400MHz,CD3OD)δ8.07(d,J=8.9Hz,2H),7.03(d,J=8.8Hz,2H),6.59–6.44(m,1H),6.29(d,J=2.0Hz,1H),5.51–5.43(m,1H),5.37–5.30(m,1H),4.61(d,J=6.3Hz,2H),4.51(d,J=7.3Hz,2H),4.18–4.02(m,2H),2.82(t,J=7.1Hz,2H),2.67–2.58(m,2H),2.10–1.96(m,2H),1.81(s,3H),1.78(s,3H),1.65(s,3H),1.58–1.52(m,5H),1.38–1.32(m,4H),0.93(t,J=6.9Hz,3H).13C NMR(100MHz,CD3OD)δ180.19,166.25,162.72,162.44,158.03,157.87,140.36,139.52,138.35,131.45(2×CH),124.12,121.00,120.29,115.34(2×CH),106.62,99.37,93.73,69.78,67.61,66.61,50.72,47.68,30.67,30.01,29.93,25.98,25.95,23.67,18.39,18.17,14.43.HRMS(ESI+):calculated for C33H44NO6[M+H]+550.3169,found 550.3161.
化合物37的制备
以化合物10(46.1mg,0.085mmol)和正辛胺(2mL)为起始原料,根据合成化合物11的方法,制备得到化合物37,为橙色油状物(36mg,72%)。1H NMR(400MHz,CD3OD)δ8.01(d,J=4.1Hz,2H),6.97(d,J=3.6Hz,2H),6.47(d,J=16.8Hz,1H),6.24(d,J=11.2Hz,1H),5.51–5.28(m,2H),4.62–4.45(m,4H),4.15–4.03(m,2H),2.85–2.74(m,2H),2.66–2.56(m,2H),2.02(s,2H),1.80(s,3H),1.76(s,3H),1.65(s,3H),1.57(s,3H),1.34–1.27(m,12H),0.89(t,J=6.6Hz,3H).13C NMR(100MHz,CD3OD)δ180.23,166.28,162.76,162.48,158.07,157.92,140.40,139.55,138.36,131.48(2×CH),124.15,121.00,120.28,115.37(2×CH),106.64,99.40,93.76,69.79,67.67,66.62,60.17,50.77,33.04,30.68,30.44,30.38,29.98,28.49,25.99,25.96,23.76,18.39,18.17,14.50.HRMS(ESI+):calculated forC36H50NO6[M+H]+592.3638,found 592.3611.
化合物38的制备
将化合物28(39.8mg,0.078mmol)溶于甲醇(8mL)溶液中,然后加入碘甲烷(1.5mL),将反应混合物在室温下搅拌过夜。反应完成后,将反应混合物用正丁醇稀释并用水萃取两次。将有机相在真空条件下浓缩。粗产物通过RP-HPLC纯化,得到化合物38,为黄色凝胶(49.2mg,71%)。1H NMR(400MHz,CD3OD)δ8.09(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),6.56(d,J=1.9Hz,1H),6.31(d,J=2.0Hz,1H),5.51–5.44(m,1H),5.36–5.28(m,1H),4.62(d,J=6.5Hz,2H),4.53(d,J=7.5Hz,2H),4.22(t,J=5.6Hz,2H),3.69–3.55(m,2H),3.22(s,9H),2.42–2.29(m,2H),1.81(s,3H),1.78(s,3H),1.64(s,3H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.34,166.44,162.76,161.94,158.20,158.04,140.63,139.78,138.39,131.60(2×CH),124.78,120.83,120.15,115.43(2×CH),106.64,99.46,93.83,69.80(2×CH2),66.64(2×CH2),53.78,53.74,53.70,25.90,25.87,24.29,18.30,18.03.HRMS(ESI+):calculated for C31H40INO6[M-I]+522.2850,found 522.2846.
化合物39的制备
以化合物15(42.7mg,0.079mmol)和碘甲烷(1.5mL)为起始原料,根据合成化合物38的方法,制备得到化合物39,为棕黄色凝胶(42.3mg,76%)。1H NMR(400MHz,CD3OD)δ8.07(d,J=8.8Hz,2H),7.06(d,J=8.8Hz,2H),6.53(d,J=1.8Hz,1H),6.28(d,J=1.7Hz,1H),5.52–5.42(m,1H),5.37–5.29(m,1H),4.61(d,J=6.5Hz,2H),4.52(d,J=7.5Hz,2H),4.21(t,J=5.4Hz,2H),3.59–3.42(m,6H),3.08(s,3H),2.35–2.22(m,2H),1.81(s,3H),1.78(s,3H),1.65(s,3H),1.57(s,3H),1.40(t,J=7.2Hz,6H).13C NMR(100MHz,CD3OD)δ180.28,166.37,162.69,161.90,158.13,157.88,140.56,139.71,138.41,131.56(2×CH),124.68,120.90,120.21,115.45(2×CH),106.65,99.46,93.83,69.82(2×CH2),66.69,65.91,58.99,57.92,57.89,25.96,25.93,23.51,18.38,18.13,8.21(2×CH3).HRMS(ESI+):calculated for C33H44INO6[M-I]+550.3163,found 550.3156.
化合物40的制备
以化合物30(45.3mg,0.079mmol)和碘甲烷(1.5mL)为起始原料,根据合成化合物38的方法,制备得到化合物40,为棕色凝胶(34mg,74%)。1H NMR(400MHz,CD3OD)δ8.08(d,J=8.4Hz,2H),7.05(d,J=8.3Hz,2H),6.60–6.48(m,1H),6.38–6.22(m,1H),5.47(t,J=6.5Hz,1H),5.32(t,J=7.4Hz,1H),4.61(d,J=6.1Hz,2H),4.52(d,J=7.4Hz,2H),4.25–4.15(m,2H),3.62–3.48(m,2H),3.38–3.33(m,4H),3.11(s,3H),2.34–2.20(m,2H),1.82–1.72(m,10H),1.65(s,3H),1.57(s,3H),1.47–1.40(m,4H),1.07–1.01(m,6H).13C NMR(100MHz,CD3OD)δ180.16,166.20,162.74,162.66,157.99,157.87,140.28,139.46,138.32,131.41(2×CH),123.87,121.04,120.29,115.34(2×CH),106.61,99.34,93.72,69.75,69.18,66.60,53.74(3×CH2),47.67,30.65,30.52,30.30,28.75,27.10,27.01,26.01,18.41,18.20,11.17(2×CH3).HRMS(ESI+):calculated for C37H52INO6[M-I]+606.3789,found 606.3785.
化合物41的制备
以化合物5(200mg,0.473mmol),溴代乙酸乙酯(105μL,0.947mmol)和碳酸钾(130.8mg,0.947mmol)为起始原料,根据合成化合物1的方法,制备得到化合物41,为黄色固体(165mg,69%)。1H NMR(400MHz,CDCl3)δ12.68(s,1H),8.09(d,J=9.3Hz,2H),7.00(d,J=9.3Hz,2H),6.43(d,J=2.5Hz,1H),6.35(d,J=2.4Hz,1H),5.84–5.23(m,2H),4.86–4.42(m,6H),4.36–4.16(m,2H),1.91–1.45(m,12H),1.31(t,J=7.3Hz,3H).13C NMR(100MHz,CDCl3)δ179.10,168.49,164.76,162.04,159.64,156.81,156.11,139.62,139.30,137.72,130.47(2×CH),124.39,119.78,118.70,114.52(2×CH),105.99,98.44,92.83,69.02,65.49,65.34,61.67,25.90,25.83,18.35,18.06,14.25.HRMS(ESI+):calculated forC29H33O8[M+H]+509.2175,found 509.2158.
化合物42的制备
以化合物5(224mg,0.53mmol),溴代乙酸乙酯(235.2μL,2.12mmol)和碳酸钾(293mg,2.12mmol)为起始原料,根据合成化合物1的方法,将反应混合物回流反应12小时,制备得到化合物42,为黄色凝胶(228.8mg,72%)。1H NMR(400MHz,CDCl3)δ8.11–8.05(m,2H),7.01–6.99(m,1H),6.99–6.97(m,1H),6.56(d,J=2.2Hz,1H),6.28(d,J=2.2Hz,1H),5.53–5.39(m,2H),4.78(s,2H),4.69(s,2H),4.60–4.53(m,4H),4.33–4.23(m,4H),1.82(s,3H),1.76(s,3H),1.68(s,3H),1.63(s,3H),1.31(t,J=5.2Hz,3H),1.28(t,J=5.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.98,168.59,168.44,162.77,159.19,159.08,158.76,152.99,140.07,139.71,139.07,130.15(2×CH),124.74,120.32,118.45,114.43(2×CH),109.98,100.00,94.68,68.74,66.82,65.46,65.39,61.63,61.47,25.92,25.82,18.34,18.17,14.25,14.22.HRMS(ESI+):calculated for C33H39O10[M+H]+595.2543,found595.2520.
化合物45的制备
将化合物41(60.4mg,0.126mmol)溶于四氢呋喃(10mL)中,然后加入LiOH(15.1mg,0.63mmol)水溶液(5mL)。将混合物在室温下搅拌1.5小时。反应完成后,将反应混合物用乙酸中和,然后用正丁醇稀释并用水萃取两次。将有机相在真空条件下浓缩,得到粗产物化合物43。化合物43无需进一步纯化即可用于下一步反应。将化合物43溶于无水DMF(5mL)中,然后加入HATU(95.6mg,0.251mmol),H-Arg-OMe·2HCl(65.6mg,0.251mmol)和DIPEA(83.1μL,0.503mmol)将混合物在室温搅拌24小时。反应完成后,然后用正丁醇稀释并用水萃取两次。将有机相在真空条件下浓缩。所得粗产物通过RP-HPLC纯化,获得化合物45,为棕色泡沫(81.8mg,74%)。1H NMR(400MHz,CD3OD)δ8.09(d,J=6.1Hz,2H),7.12(d,J=7.1Hz,2H),6.53(s,1H),6.28(s,1H),5.52–5.42(m,1H),5.33(t,J=7.4Hz,1H),4.69(s,2H),4.64–4.56(m,3H),4.53(d,J=7.3Hz,2H),3.75(s,3H),3.28–3.15(m,2H),2.06–1.74(m,8H),1.70–1.61(m,5H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.29,173.32,170.79,166.41,162.72,161.08,158.67,158.12,157.71,140.67,139.70,138.49,131.54(2×CH),125.33,120.80,120.16,115.79(2×CH),106.61,99.42,93.82,69.83,67.98,66.62,52.97,52.96,41.82,29.54,26.28,25.90,25.87,18.29,18.06.HRMS(ESI+):calculated for C34H43N4O9[M+H]+651.3030,found 651.3002.
化合物46的制备
以化合物41(60.4mg,0.126mmol),HATU(95.6mg,0.251mmol),H-His-OMe·2HCl(60.8mg,0.251mmol)和DIPEA(83.1μL,0.503mmol)为起始原料,根据合成化合物45的方法,制备得到化合物46,为黄色泡沫(59mg,86%)。1H NMR(400MHz,CD3OD)δ8.32(s,1H),8.05(d,J=7.8Hz,2H),7.16(d,J=9.6Hz,1H),7.05(d,J=7.6Hz,2H),6.52(d,J=20.4Hz,1H),6.27(d,J=19.1Hz,1H),5.46(t,J=5.7Hz,1H),5.32(t,J=7.3Hz,1H),4.87–4.84(m,1H),4.67–4.55(m,4H),4.51(d,J=7.3Hz,2H),3.75(s,3H),3.36–3.31(m,1H),3.24–3.13(m,1H),1.80(s,3H),1.77(s,3H),1.64(s,3H),1.56(s,3H).13C NMR(100MHz,CD3OD)δ180.27,172.15,170.65,166.40,162.71,160.96,158.10,157.65,140.65(2×C),139.70(2×CH),138.51,131.52(2×CH),125.35,120.81(2×CH),120.17,115.75(2×CH),106.61,99.41,93.83,69.84,67.96,66.63,53.21,52.84,28.31,25.90,25.88,18.31,18.07.HRMS(ESI+):calculated for C34H38N3O9[M+H]+632.2608,found 632.2575.
化合物47的制备
以化合物41(60mg,0.125mmol),HATU(94.9mg,0.25mmol),N,N-二甲基丙烷-1,3-二胺(31.6μL,0.25mmol)和DIPEA(82.6μL,0.50mmol)为起始原料,根据合成化合物45的方法,制备得到化合物47,为黄色固体(61.4mg,97%)。1H NMR(400MHz,CD3OD)δ8.10(d,J=7.6Hz,2H),7.12(d,J=7.7Hz,2H),6.53(s,1H),6.31–6.26(m,1H),5.47(t,J=6.5Hz,1H),5.37–5.27(m,1H),4.64(s,2H),4.61(d,J=6.5Hz,2H),4.53(d,J=7.4Hz,2H),3.40(t,J=6.5Hz,2H),3.08–3.00(m,2H),2.79(s,6H),2.00–1.91(m,2H),1.81(s,3H),1.78(s,3H),1.65(s,3H),1.57(s,3H).13C NMR(100MHz,CD3OD)δ180.32,171.22,166.44,162.77,160.97,158.15,157.67,140.65,139.74,138.55,131.62(2×CH),125.40,120.86,120.20,115.74(2×CH),106.65,99.44,93.83,69.84,68.08,66.65,56.80,43.75(2×CH3),37.14,26.33,25.93,25.90,18.33,18.08.HRMS(ESI+):calculated for C32H41N2O7[M+H]+565.2914,found 565.2916.
化合物48的制备
以化合物41(60mg,0.125mmol),HATU(197.7mg,0.25mmol),N,N-二乙基丙烷-1,3-二胺(39.3μL,0.25mmol)和DIPEA(82.6μL,0.50mmol)为起始原料,根据合成化合物45的方法,制备得到化合物48,为黄色固体(67.1mg,91%)。1H NMR(400MHz,CD3OD)δ8.08(d,J=9.0Hz,2H),7.11(d,J=8.8Hz,2H),6.54–6.49(m,1H),6.29–6.25(m,1H),5.49–5.41(m,1H),5.35–5.26(m,1H),4.62(s,2H),4.59(d,J=6.5Hz,2H),4.52(d,J=7.4Hz,2H),3.38(t,J=6.4Hz,2H),3.10(q,J=7.3Hz,4H),3.06–3.00(m,2H),1.96–1.87(m,2H),1.78(s,3H),1.75(s,3H),1.62(s,3H),1.55(s,3H),1.24(t,J=7.3Hz,6H).13C NMR(100MHz,CD3OD)δ180.31,171.20,166.44,162.78,160.97,158.15,157.65,140.66,139.74,138.53,131.61(2×CH),125.41,120.83,120.16,115.73(2×CH),106.64,99.43,93.81,69.82,68.10,66.63,50.75,48.20(2×CH2),37.35,25.91,25.88,25.51,18.30,18.05,9.34(2×CH3).HRMS(ESI+):calculated for C34H45N2O7[M+H]+593.3227,found 593.3233.
化合物50的制备
以化合物45(68.9mg,0.108mmol),HATU(82.3mg,0.216mmol),H-Arg-OMe·2HCl(50.4mg,0.216mmol)和DIPEA(71.6μL,0.433mmol)为起始原料,根据合成化合物45的方法,制备得到化合物50,为黄色凝胶(34.5mg,40%)。1H NMR(400MHz,CD3OD)δ8.11(d,J=8.5Hz,2H),7.13(d,J=8.4Hz,2H),6.56(s,1H),6.31(d,J=1.6Hz,1H),5.48(t,J=6.6Hz,1H),5.33(t,J=7.5Hz,1H),4.70(s,2H),4.62(d,J=6.4Hz,2H),4.58–4.43(m,4H),3.75–3.72(m,3H),3.25–3.13(m,4H),2.01–1.86(m,2H),1.81(s,3H),1.78(s,3H),1.77–1.60(m,9H),1.58(s,3H).13C NMR(100MHz,,CD3OD)δ180.38,173.85,173.54,170.61,166.51,162.83,161.12,158.75,158.71,158.22,157.85,140.81,139.82,138.49,131.63(2×CH),125.41,120.78,120.14,115.80,106.65,101.33,99.45,93.88,69.84,67.92,66.63,54.06,53.25,52.90,41.94,41.80,30.32,29.49,26.21,26.12,25.92,25.87,18.29,18.05.HRMS(ESI+):calculated for C40H55N8O10[M+H]+807.4041,found 807.4003.
化合物51的制备
以化合物45(58.7mg,0.092mmol),HATU(87.6mg,0.23mmol),N,N-二甲基-1,3-丙二胺(69.6μL,0.553mmol)和DIPEA(76μL,0.46mmol)为起始原料,根据合成化合物45的方法,制备得到化合物51,为黄色固体(35.1mg,53%)。1H NMR(400MHz,CD3OD)δ8.11(d,J=8.8Hz,2H),7.15(d,J=8.9Hz,2H),6.57(d,J=2.0Hz,1H),6.31(d,J=2.1Hz,1H),5.48(t,J=6.6Hz,1H),5.33(t,J=7.5Hz,1H),4.72(s,2H),4.62(d,J=6.5Hz,2H),4.55(d,J=7.5Hz,2H),4.40–4.31(m,1H),3.31–3.17(m,4H),3.08(t,J=7.7Hz,2H),2.81(s,6H),1.99–1.82(m,4H),1.81(s,3H),1.78(s,3H),1.72–1.62(m,5H),1.58(s,3H).13C NMR(100MHz,CD3OD)δ180.34,174.48,170.86,166.48,162.80,161.14,158.73,158.20,157.80,140.75,139.78,138.49,131.61(2×CH),125.36,120.78,120.13,115.77(2×CH),106.64,99.44,93.85,69.83,67.93,66.62,56.39,54.61,43.42(2×CH3),41.86,37.04,29.96,26.38,25.91,25.88,25.86,18.28,18.04.HRMS(ESI+):calculated for C38H53N6O8[M+H]+721.3925,found 721.3906.
化合物52的制备
以化合物42(189mg,0.351mmol),HATU(533.8mg,1.40mmol),H-Arg-OMe·2HCl(366.6mg,1.40mmol)和DIPEA(464μL,2.81mmol)为起始原料,根据合成化合物45的方法,制备得到化合物52,为黄色凝胶(146mg,47%)。1H NMR(400MHz,,CD3OD)δ8.12(d,J=8.5Hz,2H),7.15(d,J=8.7Hz,2H),6.76(s,1H),6.48(s,1H),5.49(t,J=6.4Hz,1H),5.37–5.30(m,1H),4.73–4.63(m,6H),4.60–4.44(m,4H),3.75(s,3H),3.75(s,3H),3.30–3.18(m,4H),2.11–1.76(m,12H),1.69–1.63(m,5H),1.56(s,3H).13C NMR(100MHz,CD3OD)δ176.12,173.49,173.41,170.92,170.84,169.34,165.36,161.05,159.75,159.13,158.72,155.90,140.64,140.40,140.05,131.41(2×CH),125.29,120.81,119.97,115.88(2×CH),109.59,99.36,95.96,69.78,69.14,67.98,66.89,53.29,53.07,52.98(2×CH3),42.01,41.81,29.56,29.51,26.32,26.18,25.96,25.90,18.36,18.24.HRMS(ESI+):calculated forC43H59N8O12[M+H]+879.4252,found 879.4223.
化合物53的制备
以化合物42(70mg,0.130mmol),HATU(197.7mg,0.52mmol),N,N-二甲基丙烷-1,3-二胺(65.4μL,0.52mmol)和DIPEA(171.8μL,1.04mmol)为起始原料,根据合成化合物45的方法,制备得到化合物53,为黄色凝胶(69.6mg,76%)。1H NMR(400MHz,CD3OD)δ8.10(d,J=8.3Hz,2H),7.11(d,J=8.3Hz,2H),6.72(s,1H),6.45(s,1H),5.53–5.40(m,1H),5.32(t,J=7.2Hz,1H),4.64(d,J=5.4Hz,2H),4.59(s,4H),4.50(d,J=7.3Hz,2H),3.41(t,J=6.7Hz,2H),3.34–3.30(m,2H),2.63–2.54(m,2H),2.40(t,J=7.5Hz,2H),2.34(s,6H),2.26(s,6H),1.92–1.83(m,2H),1.79(s,3H),1.77(s,3H),1.75–1.69(m,2H),1.63(s,3H),1.55(s,3H).13C NMR(100MHz,CD3OD)δ176.17,171.25,169.83,165.38,160.89,159.82,159.23,156.03,140.47,140.39,140.04,131.49(2×CH),125.41,120.97,119.96,115.79(2×CH),109.65,99.53,95.90,69.69,69.29,68.07,66.88,56.69,56.56,43.58(2×CH3),43.49(2×CH3),37.00,36.97,26.08,25.97,25.91,25.88,18.33,18.15.HRMS(ESI+):calculatedfor C39H55N4O8[M+H]+707.4020,found 707.3997.
化合物54的制备
以化合物42(70mg,0.130mmol),HATU(197.7mg,0.52mmol),N,N-二乙基丙烷-1,3-二胺(82.0μL,0.52mmol)和DIPEA(171.8μL,1.04mmol)为起始原料,根据合成化合物45的方法,制备得到化合物54,为黄色凝胶(74.7mg,75%)。1H NMR(400MHz,CD3OD)δ8.12(d,J=8.3Hz,2H),7.14(d,J=8.3Hz,2H),6.72(s,1H),6.44(s,1H),5.51–5.43(m,1H),5.35(t,J=7.6Hz,1H),4.68–4.59(m,6H),4.51(d,J=7.3Hz,2H),3.51(t,J=5.8Hz,2H),3.42(t,J=6.4Hz,2H),3.28–3.10(m,12H),2.14–2.04(m,2H),2.03–1.94(m,2H),1.81(s,3H),1.78(s,3H),1.66(s,3H),1.57(s,3H),1.34–1.28(m,12H).13C NMR(100MHz,CD3OD)δ176.23,171.22,169.70,165.44,160.92,159.86,159.30,156.11,140.48,140.43,140.10,131.51(2×CH),125.44,120.97,119.93,115.81(2×CH),109.68,99.62,95.96,69.68,69.39,68.11,66.89,50.83,50.60,48.35(2×CH2),48.19(2×CH2),37.18(2×CH2),25.92,25.87,25.29,25.27,18.32,18.13,9.18(2×CH3),9.08(2×CH3).HRMS(ESI+):calculated forC43H63N4O8[M+H]+763.4646,found 763.4614.
化合物56的制备
以化合物52(40.3mg,0.047mmol),HATU(72.2mg,0.189mmol),H-Arg-OMe·2HCl(49.5mg,0.189mmol)和DIPEA(62.6μL,0.379mmol)为起始原料,根据合成化合物45的方法,制备得到化合物56,为黄色凝胶(22mg,39%)。1H NMR(400MHz,CD3OD)δ8.13(d,J=8.9Hz,2H),7.16(d,J=8.9Hz,2H),6.81(s,1H),6.53(s,1H),5.54–5.48(m,1H),5.36–5.30(m,1H),4.73–4.66(m,6H),4.57–4.41(m,6H),3.73(s,3H),3.73(s,3H),3.35–3.35(m,2H),3.26–3.13(m,6H),2.11–1.62(m,26H),1.56(s,3H).13C NMR(100MHz,,CD3OD)δ176.13,174.07,173.92,173.60,173.55,170.90,170.59,169.65,165.34,160.95,159.76,159.11,158.70,158.68,158.66,155.88,140.69,140.37,140.01,131.45(2×CH),125.22,120.73,119.96,115.84,109.56,101.30,99.29,95.92,69.92,69.12,67.88,66.90,54.44,54.12,53.35,53.26,52.91,52.90,42.16,41.91,41.81,41.80,30.29,30.11,29.46,29.40,26.22,26.09,26.05,25.98(2×CH2),25.90,18.36,18.29.HRMS(ESI+):calculated forC55H84N16O14[M+2H]2+596.3177,found 596.3165.
生物实验评估方法
抗菌活性测定
最低抑菌浓度(MIC)是依据临床和实验室标准协会(CLSI)指南通过肉汤微稀释法测定。将细菌细胞接种到Mueller-Hinton琼脂(MHA)平板上,于37℃培育24小时,并调整细菌细胞浓度至大约1×106CFU/mL。将样品首先溶解在DMSO/H2O中以制备样品储备液(DMSO的最终浓度≤2%)。用Mueller-Hinton Broth(MHB)培养基将样品稀释至初始浓度100μg/mL,然后将样品(100μL)通过两倍梯度稀释加到96孔板中,随后将等体积(100μL)的细菌悬浮液(1×106CFU/mL)添加到96孔板的各孔中。最后将96孔板在37℃下孵育24小时。将抑制细菌生长的最低样品浓度记录为MIC值。MIC值是通过测量OD600和肉眼观察确定。所有实验至少进行两次,并可实现生物学重复。
溶血活性测定
将兔红细胞以2500rpm离心3分钟,然后用PBS洗涤两次。随后,将兔红细胞悬浮在PBS中以制备6%(v/v)悬浮液。将样品溶解在DMSO或PBS中,然后用PBS稀释以制备两倍梯度稀释液。将兔红细胞悬浮液(100μL)与样品的两倍梯度稀释液(100μL)混合,并于37℃孵育1小时。混合悬浮液中DMSO和兔红细胞的最终浓度分别控制在0.5%和3%。然后,将混合悬浮液以2500rpm离心5分钟,并将上清液(100μL)转移到96孔板中。使用Biotek多功能酶标仪测定576nm处的吸光度,以2%Triton X-100溶液处理组用作阳性对照;以PBS或0.5%DMSO处理组用作阴性对照。通过以下等式计算溶血活性:%溶血活性=[(Abs样品–Abs阳性对照)/(Abs阳性对照–Abs阳性对照)]×100。所有实验至少进行两次,并可实现生物学重复。
耐药性发展倾向评估
通过上述MIC测定方法获得化合物45和52对金黄色葡萄球菌ATCC29213的初始MIC。然后使用浓度为0.5×MIC的96孔板中的细菌细胞制备细菌悬浮液(~106CFU/mL),用于下一次MIC的测量。与样品于37℃孵育24小时后,确定新的MIC值。该实验连续进行19天。
体内功效评估
动物体内抗菌功效评估实验已获得华南农业大学实验动物中心的批准,并按照卫生部的政策进行。所使用小鼠为雌性C57BL6小鼠(6-8周,约20g)。首先将细菌细胞(金黄色葡萄球菌ATCC29213)接种到Mueller-Hinton琼脂(MHA)平板上,于37℃培育24小时后,将菌落浓度调整至约5×107CFU/mL,留待小鼠角膜感染时使用。
首先制备小鼠免疫抑制模型,在感染前5天通过腹腔注射环磷酰胺(100mg/kg)3次。将小鼠麻醉,随后用无菌针头对小鼠左眼的角膜进行划痕(n=4,每1毫米长)。然后将15μL细菌滴到受伤的角膜上。感染一天后,将这些小鼠随机分为三组(每组5只小鼠)。并每天分别滴化合物(5%万古霉素,0.5%化合物52或5%葡萄糖)溶液四次,持续滴三天。最终将小鼠处死。最后收集感染的角膜并将其铺在MHA板上以计数活菌的数量。
3、实验结果
抗菌和溶血活性结果如表1和2所示。
其中化合物52和56对革兰氏阳性菌表现出非常优异的抗菌活性,MIC值为1.56-3.125μg/mL;同时对兔红细胞展示出非常低的溶血活性,HC50(裂解50%兔红细胞所需化合物的浓度)值>200μg/mL。该结果表明化合物52和56都具有非常高的膜选择性(HC50/MIC)。
表1.基于山萘酚的黄酮衍生物化合物1-40的体外抗菌和溶血活性(μg/mL)
Figure BDA0002310809240000301
Figure BDA0002310809240000311
表2.基于山萘酚的黄酮衍生物化合物45-56的体外抗菌和溶血活性(μg/mL)
Figure BDA0002310809240000312
耐药性研究结果
耐药性的发展倾向已成为设计和评估新型抗菌药物的关键因素。如图1所示,经过19次传代后,化合物45和52的MIC均未观察到>4倍的增加。相反,诺氟沙星(Norfloxacin)则迅速地产生耐药性,经过15次传代后MIC值增加了128倍。这些结果表明,化合物45和52可以有效减缓甚至克服细菌耐药性的产生。
体内抗菌活性评估结果
化合物52对革兰氏阳性菌表现出优异的体外抗菌活性,并具有非常高的膜选择性。在本研究中,通过环磷酰胺处理制备了小鼠免疫抑制模型,然后用金黄色葡萄球菌ATCC29213感染小鼠角膜。感染后一天,将小鼠随机分为三组(每组五只小鼠),每组小鼠分别用0.5%的化合物52、5%的万古霉素(阳性对照)或5%的葡萄糖(阴性对照)进行局部处理。每天对小鼠进行4次治疗,共3天。如图2所示,化合物52和万古霉素分别使感染的角膜中的金黄色葡萄球菌数量减少3.28log(p=0.03)和3.99log(p=0.029)。化合物52显示出可与万古霉素相互比拟的体内抗菌活性,尽管其浓度比万古霉素低十倍。这些结果表明,化合物52能够治愈由金黄色葡萄球菌引起的小鼠角膜感染。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。

Claims (8)

1.黄酮类化合物,其特征在于,具有式(IV)所示结构
Figure FDA0003902471950000011
R3和R4各自独立地为H、
Figure FDA0003902471950000012
且R3和R4不同时为氢;
其中,m1为1、2或3;
n1为1、2、3、4或5;R14选自胍基或-NR5R6;R15选自H或C1-6烷基;
R12和R13各自独立地选自H、
Figure FDA0003902471950000013
其中,n2为1、2、3、4或5,R24选自H、胍基或-NR5R6;R25选自H或C1-6烷基;
R40为胍基或-NR5R6,p为1、2、3、4或5;
R5和R6各自独立地选自:H或C1-6烷基。
2.根据权利要求1所述的黄酮类化合物,其特征在于,所述黄酮类化合物为两亲性的阳离子型化合物。
3.根据权利要求1所述的黄酮类化合物,其特征在于,选自以下化合物:
Figure FDA0003902471950000014
Figure FDA0003902471950000021
4.权利要求1-3任一项所述的黄酮类化合物的制备方法,其特征在于,包括以下步骤:
使式(I-1)所示化合物和卤代烷烃或卤代烯烃发生取代反应,生成式(I-2)所示化合物;
使式(I-2)所示化合物和
Figure FDA0003902471950000022
反应,制得式(I-3)所示化合物;
使式(I-3)所示化合物中的酯基水解成羧酸,制得式(I-4)所示化合物;
使式(I-4)所示化合物和
Figure FDA0003902471950000023
反应,制得式(I-5)所示化合物;
Figure FDA0003902471950000024
其中,R1和R2各自独立地选自
Figure FDA0003902471950000025
Figure FDA0003902471950000026
中X表示卤素;
R3′和R4′各自独立地为H或
Figure FDA0003902471950000027
且R3′和R4′不同时为H;
R5′和R6′各自独立地为H或
Figure FDA0003902471950000028
且R5′和R6′不同时为H;
R7′和R8′各自独立地为H或
Figure FDA0003902471950000029
且R7′和R8′不同时为H;
其中,R14、R15、m1和n1如权利要求1所定义。
5.根据权利要求4所述的制备方法,其特征在于,制得式(I-5)所示化合物的步骤后还包括以下步骤:
使式(I-5)所示化合物中酯基水解成羧酸,制得式(I-6)所示化合物;
使式(I-6)所示化合物和
Figure FDA0003902471950000031
反应,制得式(I-7)所示化合物;
Figure FDA0003902471950000032
R9′和R10′各自独立地为H或
Figure FDA0003902471950000033
且R9′和R10′不同时为H;
R11′和R12′各自独立地为H或
Figure FDA0003902471950000034
且R11′和R12′不同时为H;
其中,R24、R25和n2如权利要求1所定义。
6.权利要求1-3任一项所述的黄酮类化合物及其药学上可接受的盐在制备抗菌药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述的抗菌药物为治疗革兰氏阳性细菌导致疾病的药物。
8.根据权利要求7所述的应用,其特征在于,所述革兰氏阳性细菌为耐甲氧西林金黄色葡萄球菌。
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