CN114790185B - 一种香豆素肟酯类化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
一种香豆素肟酯类化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
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- CN114790185B CN114790185B CN202210464434.1A CN202210464434A CN114790185B CN 114790185 B CN114790185 B CN 114790185B CN 202210464434 A CN202210464434 A CN 202210464434A CN 114790185 B CN114790185 B CN 114790185B
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- compound
- oxime ester
- ester compound
- pharmaceutically acceptable
- coumarin
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- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
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- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000003684 Perkin reaction Methods 0.000 claims description 2
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Abstract
本发明涉及一种香豆素肟酯类化合物或其药学上可接受的盐及其制备方法和应用。所述香豆素肟酯类化合物具有如式I所示的结构：其中，R1选自取代的芳香基、取代或未取代的杂芳基、取代或未取代的苯乙烯基；R2和R3独立地选自H、卤素、C1～10的烷基、C1～10的烷氧基。本发明以取代水杨醛结构为母核，设计并合成了一系列香豆素肟酯类化合物，所述香豆素肟酯类化合物表现出强的α‑葡萄糖苷酶抑制作用，IC50值最低为2.54μM，是阿卡波糖的100～150倍，能够作为α‑葡萄糖苷酶抑制剂用于治疗或预防糖尿病。
Description
技术领域
本发明属于药物化学技术领域，尤其涉及一种香豆素肟酯类化合物或其药学上可接受的盐及其制备方法和应用。
背景技术
2021年12月6日，国际糖尿病联盟(IDF)发布了《IDF世界糖尿病地图(第10版)》，其中包括2021年全球糖尿病的九大数据：每10个20～79岁的成年人中就有1名糖尿病患者，总数达5.37亿人；每2名糖尿病患者中有1名未被确诊，总数达2.40亿人；每4名糖尿病患者中有3名生活在中低收入国家或地区；每18个20～79岁的成年人中就有1名空腹血糖受损，总数达3.19亿；每6个活产儿中有1个受妊娠期高血糖的影响，总数达2100万，80％孩子的母亲有妊娠期糖尿病；120万20岁以下的儿童青少年患有1型糖尿病；每9个20～79岁的成年人中就有1名糖耐量受损，总数达5.41亿人；全世界9％的健康支出花在了糖尿病上，总额达9.66亿美元；670万人死于糖尿病。
糖尿病是一种由于胰岛素分泌不足，或者胰岛β细胞损害，致使血糖水平升高的慢性代谢紊乱疾病。糖尿病导致的患者体内长期血糖浓度过高，可能引起一系类并发症，例如，血糖水平的增加可能会导致许多微血管和大血管的并发症。其中，微血管并发症包括视网膜病变、白内障、肾病、神经病，而大血管并发症包括中风、心血管疾病、冠状动脉疾病、脑血管疾病和糖尿病足，糖尿病足严重时可能导致截肢。目前临床上应用的降糖药物主要有磺脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类和非磺脲类胰岛素促分泌剂等。
α-葡萄糖苷酶抑制剂通过抑制小肠黏膜刷状缘的α-葡萄糖苷酶以延缓碳水化合物的吸收，降低餐后高血糖。主要特点包括平稳降糖、安全性高，以及可降低心血管并发症的发生率，是少数可干预糖耐量受损的口服降糖药之一。α-葡萄糖苷酶抑制剂的降糖机制是，通过抑制肠黏膜上的α-葡萄糖苷酶，使淀粉分解为葡萄糖的速度减缓，减少和延缓小肠对葡萄糖的吸收，以降低血糖，对餐后高血糖的作用比较明显。葡萄糖苷酶抑制剂不刺激胰岛素的分泌，单独使用本类药物通常不会引发低血糖，因此可帮助减少血糖的波动。可以明显降低糖尿病患者发生心血管病变的概率，对心肌梗死的改善作用最为显著。
因此，有必要提供一系列具有高α-葡萄糖苷酶抑制活性的化合物。
发明内容
本发明旨在至少解决现有技术中存在的上述技术问题之一。为此，本发明提供了一种香豆素肟酯类化合物或其药学上可接受的盐。
本发明还提供了一种香豆素肟酯类化合物或其药学上可接受的盐的制备方法。
本发明还提供了一种香豆素肟酯类化合物或其药学上可接受的盐的应用。
本发明的第一方面提供了香豆素肟酯类化合物或其药学上可接受的盐，所述香豆素肟酯类化合物具有如式I所示的结构：
其中，R1选自取代的芳香基、取代或未取代的杂芳基、取代或未取代的苯乙烯基；R2和R3独立地选自H、卤素、C1～10的烷基、C1～10的烷氧基。
本发明关于香豆素肟酯类化合物或其药学上可接受的盐的技术方案中的一个技术方案，至少具有以下有益效果：
本发明以取代水杨醛结构为母核，设计并合成了一系列香豆素肟酯类化合物，所述香豆素肟酯类化合物表现出强的α-葡萄糖苷酶抑制作用，IC50值最低为2.54μM，是阿卡波糖的100～150倍，能够作为α-葡萄糖苷酶抑制剂用于治疗或预防糖尿病。
根据本发明的一些实施方式，所述R1选自取代地的苯基、吡啶基、呋喃基、噻吩基、取代或未取代地的苯乙烯基。
根据本发明的一些实施方式，所述香豆素肟酯类化合物选自如下结构中的一种：
本发明的第二方面提供一种上述所述的香豆素肟酯类化合物或其药学上可接受的盐的制备方法，包括如下步骤：
S1、将化合物a与乙酰乙酸乙酯进行Perkin反应，得到中间体1；
S2、将所述中间体1与盐酸羟胺进行反应，得到中间体2；
S3、将所述中间体2与化合物b进行酯化反应得到式I所示的香豆素肟酯类化合物；其中，所述化合物a、中间体1、中间体2、化合物b的结构式如下：
根据本发明的一些实施方式，步骤S1中，所述化合物a与所述乙酰乙酸乙酯的摩尔比为1：(1.1～2)。
根据本发明的一些实施方式，步骤S1中，所述反应的温度70℃～100℃，反应的时间2h～4h。
根据本发明的一些实施方式，步骤S2中，所述中间体1和所述盐酸羟胺的摩尔比为1：(2.5～3.0)。
根据本发明的一些实施方式，步骤S2中，所述反应的温度为室温，反应的时间15h～20h。
根据本发明的一些实施方式，步骤S3中，所述中间体2和所述化合物b的摩尔比为1：(1.2～1.5)。
根据本发明的一些实施方式，步骤S3中，所述反应的温度为室温，所述反应的时间10h～h。
本发明的第三方面提供一种药物组合物，包含上述任一项所述的香豆素肟酯类化合物或其药学上可接受的盐，及其药学上可接受的辅料。
本发明的第四方面提供上述所述的香豆素肟酯类化合物或其药学上可接受的盐或上述所述的药物组合物在制备预防和/或治疗糖尿病的产品中的应用。
根据本发明的一些实施方式，所述产品包括药物或保健品中的至少一种。
定义和一般术语
本发明使用的术语“药学上可接受”是指从毒理学观点来看可接受用于制药应用且不会与活性成分发生不利地相互作用的物质。
“C1～10的烷基”表示碳原子总数为1～10的烷基，包括C1～10的直链烷基、C1～10的支链烷基和C3～10的环烷基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9或10的直链烷基、碳原子总数为1、2、3、4、5、6、7、8、9或10的支链烷基或者碳原子总数为3、4、5、6、7、8、9或10的环烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。
“C1～10的烷氧基”表示碳原子总数为1～10的烷氧基，包括C1～10的直链烷氧基、C1～10的支链烷氧基和C2～10的环烷氧基，例如可以为碳原子总数为1、2、3、4、5、6、7、8、9或10的直链烷氧基、碳原子总数为1、2、3、4、5、6、7、8、9或10的支链烷氧基或者碳原子总数为2、3、4、5、6、7、8、9或10的环烷氧基，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基等。
“卤素”为氟、氯、溴、碘。
“取代的芳香基”表示芳香基中至少有一个氢被本文定义的相应基团所取代。例如取代的苯基、取代的萘基、取代的蒽基。
“杂芳基”表示含有从1个至4个选自由O、N和S组成的杂原子芳香族基团。在该定义的范围内的杂芳基基团包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基和四氢喹啉。
“取代或未取代的苯乙烯基”表示苯乙烯基中至少有一个氢被本文定义的相应基团所取代。
本文使用的“取代或未取代的”是指基团可以被或可以不被一个或更多个选自以下的基团进一步取代：烷基、烯基、炔基、芳基、卤素、卤代烷基、卤代烯基、卤代炔基、卤代芳基、羟基、烷氧基、烯氧基、芳氧基、苄氧基、卤代烷氧基、卤代烯氧基、卤代芳氧基、硝基、硝基烷基、硝基烯基、硝基炔基、硝基芳基、硝基杂环基、氨基、烷基氨基、二烷基氨基、烯基氨基、炔基氨基、芳基氨基、二芳基氨基、苯基氨基、二苯基氨基、苄基氨基、二苄基氨基、肼基、酰基、酰氨基、二酰氨基、酰氧基、杂环基、杂环氧基、杂环基氨基、卤代杂环基、羧基酯、羧基、羧基酰胺、巯基、烷硫基、苄硫基、酰硫基和含磷基团。
像本发明所描述的包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂、助流剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practiceof Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrickand J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
本发明化合物或药学上可接受的盐的药物组合物，可以用以下所述的任意方式给与：口服给药、喷雾吸入法、局部给药、经直肠给药、经鼻给药、局部给药、阴道给药、非肠道给药如皮下、静脉、肌内、腹腔内、鞘内、心室内、胸骨内、或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药、肌注、向腹膜内给药或静脉注射。
本发明化合物或药学上可接受的盐或含有药学上可接受的组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆、阿拉伯胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮；填充剂，如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇、氨基乙酸；润滑剂，如硬脂酸镁、滑石、聚乙二醇、硅土；崩解剂，如马铃薯淀粉；或可接受的增润剂如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水合油的悬浮液、溶液、乳浊液、糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂、山梨醇、纤维素甲醚、葡萄糖糖浆、凝胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化的食用油脂、乳化剂，如卵磷脂、山梨聚醣单油酸盐、阿拉伯胶；或非水载体(可能包含可食用油)，如杏仁油，油脂如甘油、乙二醇、或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯、山梨酸。如需要可添加调味剂或着色剂。
附图说明
图1为本发明实验例1中化合物19作为α-葡萄糖苷酶抑制剂在体外对α-葡萄糖苷酶的酶动力学图；
图2为本发明实验例2中化合物19作为α-葡萄糖苷酶抑制剂在体外对α-葡萄糖苷酶的底物动力学图；(a)为双倒数作图法作出的底物动力学图；(b)为截距图；
图3为本发明实验例3中化合物19与α-葡萄糖苷酶的相互作用规律分子对接图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，但本发明的实施方式不限于此。
本发明所采用的试剂、方法和设备，如无特殊说明，均为本技术领域常规试剂、方法和设备。
实施例1
实施例1提供一种香豆素肟酯类化合物，其结构式如下，制备方法如下：
S1、将化合物a(1.0mmol)、乙酰乙酸乙酯(1.1mmol)和哌啶(0.02mmol)在乙醇(10mL)中的混合物在70℃下搅拌2h。反应完成后，将混合物倒入冰水中，然后过滤以获得粗产物。然后用乙醇重结晶得到取代乙酰香豆素，得到中间体1；
S2、将所述中间体1(1.0mmol)、盐酸羟胺(3.0mmol)和吡啶(0.04mmol)在乙醇(10mL)中的混合物在室温下搅拌20h。将产生的固体过滤并用乙醇洗涤以产生含有取代乙酰香豆素的肟，得到中间体2；
S3、向DCM(3mL)中含有中间体2(1.0mmol)和三乙胺(1.1)的冰浴溶液中添加DCM(3mL)中的化合物b的氯化物(1.2mmol)，然后在升温至室温后反应12小时。用水淬火后，混合物用二氯化钠萃取三次，用盐水洗涤，用硫酸镁干燥。在真空下去除溶剂以获得粗产物，然后通过柱层析纯化以得到化合物1。
其中，化合物a、中间体1、中间体2和化合物b的结构式如下：
其中，化合物1的核磁、质谱数据如下：
(化合物1,C19H15NO4).Yield 70％；m.p.160-161℃；1H NMR(500MHz,Chloroform-d)δ8.20(s,1H),8.02(d,J＝8.0Hz,2H),7.59(t,J＝7.6Hz,2H),7.37(d,J＝8.3Hz,1H),7.35-7.28(m,3H),2.55(s,3H),2.44(s,3H)；13C NMR(126MHz,CDCl3)δ163.76,162.54,159.21,154.35,144.86,143.46,133.06,129.07,128.47,126.00,125.97,124.99,123.42,118.49,117.96,116.70,77.32,77.07,76.81,15.97；HRMS(ESI)[M+H]+calcd.forC19H15NO4:322.1071；found:322.1084.
实施例2
实施例2提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物2的核磁、质谱数据如下：
(化合物2,C18H12ClNO4).Yield 70％；m.p.185-186℃；1H NMR(500MHz,Chloroform-d)δ8.19(s,1H),8.06(dd,J＝8.5,1.6Hz,2H),7.61-7.57(m,2H),7.49(dd,J＝8.4,1.6Hz,2H),7.39-7.31(m,2H),2.55(d,J＝1.5Hz,3H)；13C NMR(126MHz,CDCl3)δ162.98,162.81,159.23,154.38,143.59,140.23,133.12,131.13,129.12,127.07,125.02,123.33,118.48,116.74,77.31,77.26,77.05,76.80,16.09；HRMS(ESI)[M+H]+calcd.forC18H12ClNO4:342.0525；found:342.0536.
实施例3
实施例3提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物3的核磁、质谱数据如下：
(化合物3，C18H12BrNO4).Yield 69％；m.p.180-182℃；1H NMR(500MHz,Chloroform-d)δ8.18(s,1H),8.00-7.97(m,2H),7.66-7.64(m,2H),7.62-7.57(m,2H),7.38-7.31(m,2H),2.54(s,3H)；13C NMR(126MHz,CDCl3)δ163.01,162.94,159.20,154.38,143.58,133.12,132.11,131.22,129.11,128.91,127.53,125.02,123.31,118.48,116.73,77.32,77.07,76.81,16.08；HRMS(ESI)[M+H]+calcd.for C18H12BrNO4:387.9997；found:388.0004.
实施例4
实施例4提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物4的核磁、质谱数据如下：
(化合物4,C18H12FNO4).Yield 68％；m.p.208-209℃；1H NMR(500MHz,Chloroform-d)δ8.19(s,1H),8.17-8.14(m,2H),7.61-7.58(m,2H),7.39-7.31(m,2H),7.19(t,J＝8.6Hz,2H),2.55(s,3H)；13C NMR(126MHz,CDCl3)δ167.17,165.13,162.82,162.67,159.23,154.39,143.54,133.08,132.41,132.33,129.10,125.00,124.89,124.86,123.38,118.51,116.73,116.08,115.90,77.30,77.25,77.04,76.79,16.04；HRMS(ESI)[M+H]+calcd.forC18H12FNO4:326.0820；found:326.0832.
实施例5
实施例5提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物5的核磁、质谱数据如下：
(化合物5,C19H15NO5).Yield 65％；m.p.165-167℃；1H NMR(500MHz,Chloroform-d)δ8.20(s,1H),8.10–8.08(m,2H),7.59(d,J＝7.7Hz,2H),7.39-7.31(m,2H),7.00-6.97(m,2H),3.90(s,3H),2.54(s,3H)；13C NMR(126MHz,CDCl3)δ163.93,163.38,162.21,159.33,154.36,143.45,132.97,131.90,129.08,124.97,123.60,120.79,118.57,116.70,114.00,77.30,77.25,77.05,76.79,55.56,16.00；HRMS(ESI)[M+H]+calcd.for C19H15NO5:338.1019；found:338.1033.
实施例6
实施例6提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物6的核磁、质谱数据如下：
(化合物6，C18H12N2O6).Yield 65％；m.p.244-245℃；1H NMR(500MHz,Chloroform-d)δ8.38–8.36(m,2H),8.32–8.29(m,2H),8.19(s,1H),7.64-7.59(m,2H),7.40-7.33(m,2H),2.58(s,3H)；13C NMR(126MHz,CDCl3)δ163.82,161.81,159.13,154.43,150.89,143.74,134.15,133.30,130.89,129.16,127.73,125.09,123.89,123.80,123.04,118.40,116.78,77.30,77.25,77.05,76.79,16.20；HRMS(ESI)[M+H]+calcd.for C19H15NO5:338.1019；found:338.1033.
实施例7
实施例7提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物7的核磁、质谱数据如下：
(化合物7，C19H12F3NO4).Yield 69％；m.p.168-170℃；1H NMR(500MHz,DMSO-d6)δ8.37(s,1H),8.03–8.01(m,2H),7.91(dd,J＝7.8,1.7Hz,1H),7.83-7.81(m,2H),7.71(ddd,J＝8.8,7.4,1.7Hz,1H),7.51-7.47(m,1H),7.43(td,J＝7.5,1.1Hz,1H),2.45(s,3H)；13CNMR(126MHz,DMSO)δ163.93,162.59,159.07,154.24,143.92,133.74,132.69,131.84,130.08,128.58,127.85,125.48,123.43,118.83,116.71,40.45,40.38,40.29,40.21,40.12,40.04,39.95,39.87,39.79,39.62,39.45,16.35；HRMS(ESI)[M+H]+calcd.forC19H15NO4:402.0944；found:402.0951.
实施例8
实施例8提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物8的核磁、质谱数据如下：
(化合物8，C18H13NO5).Yield 68％；m.p.159-160℃；1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.36(s,1H),7.98-7.94(m,2H),7.91(dd,J＝7.8,1.6Hz,1H),7.74-7.69(m,1H),7.50(d,J＝8.3Hz,1H),7.43(t,J＝7.5Hz,1H),6.96-6.90(m,2H),2.43(s,3H)；13CNMR(126MHz,DMSO)δ163.08,162.98,162.77,159.17,154.20,143.71,133.63,132.28,130.02,125.46,123.71,118.94,118.88,116.69,116.18,40.45,40.37,40.28,40.21,40.12,40.04,39.95,39.87,39.78,39.62,39.45,16.22；HRMS(ESI)[M+H]+calcd.for C18H13NO5:324.0863；found:324.08.
实施例9
实施例9提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物9的核磁、质谱数据如下：
(化合物9，C20H15NO4).Yield 67％；m.p.161-162℃；1H NMR(500MHz,Chloroform-d)δ8.16(s,1H),7.88(d,J＝16.0Hz,1H),7.62-7.55(m,4H),7.45-7.38(m,3H),7.38-7.29(m,2H),6.59(d,J＝16.0Hz,1H),2.49(s,3H)；13C NMR(126MHz,CDCl3)δ164.32,162.14,159.26,154.34,146.84,143.39,134.14,132.96,130.85,129.06,129.02,128.35,124.95,123.58,118.55,116.68,115.29,77.32,77.06,76.81,15.94；HRMS(ESI)[M+H]+calcd.forC20H15NO4:334.1070；found:334.1074.
实施例10
实施例10提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物10的核磁、质谱数据如下：
(化合物10，C21H17NO4).Yield 62％；m.p.154-155℃；1H NMR(500MHz,DMSO-d6)δ8.34(s,1H),7.90(dd,J＝7.8,1.6Hz,1H),7.81(d,J＝16.1Hz,1H),7.69(dd,J＝7.5,4.0Hz,3H),7.48(d,J＝8.3Hz,1H),7.42(td,J＝7.5,1.1Hz,1H),7.27(d,J＝7.8Hz,2H),6.79(d,J＝16.0Hz,1H),2.38(s,3H),2.34(s,3H).13C NMR(126MHz,DMSO)δ164.18,162.56,159.13,154.19,146.68,143.72,141.46,133.63,131.70,130.07,130.02,129.14,125.45,123.64,118.87,116.68,114.93,40.48,40.39,40.31,40.23,40.14,40.05,39.98,39.88,39.81,39.64,39.47,21.56,16.15.HRMS(ESI)[M+H]+calcd.for C21H17NO4:348.1229；found:348.1233.
实施例11
实施例11提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物11的核磁、质谱数据如下：
(化合物12，C20H14ClNO4).Yield 65％；m.p.248-249℃；1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.83(d,J＝16.0Hz,1H),7.63-7.55(m,2H),7.55-7.49(m,2H),7.41-7.29(m,4H),6.56(d,J＝16.0Hz,1H),2.48(s,3H).13C NMR(126MHz,CDCl3)δ164.09,162.28,159.24,154.32,145.34,143.43,136.78,133.02,132.60,129.52,129.32,129.07,124.98,123.49,118.50,116.69,115.86,77.35,77.09,76.84,15.97.HRMS(ESI)[M+H]+calcd.for C20H14ClNO4:368.0682,found:368.0687.
实施例12
实施例12提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物12的核磁、质谱数据如下：
(化合物12，C20H14BrNO4).Yield 69％；m.p.182-183℃；1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.81(d,J＝16.0Hz,1H),7.62-7.53(m,4H),7.52–7.43(m,2H),7.38-7.30(m,2H),6.58(d,J＝16.0Hz,1H),2.48(s,3H)；13C NMR(126MHz,CDCl3)δ164.10,162.31,159.26,154.34,145.44,143.45,133.03,132.29,129.71,129.09,125.20,124.99,123.50,118.52,116.71,115.97,77.31,77.26,77.06,76.80,15.98.HRMS(ESI)[M+H]+calcd.For C20H14BrNO4:412.0187；found:412.0181.
实施例13
实施例13提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物13的核磁、质谱数据如下：
(化合物13，C20H14FNO4).Yield 67％；m.p.166-170℃；1H NMR(500MHz,Chloroform-d)δ8.14(s,1H),7.84(d,J＝16.0Hz,1H),7.58(ddd,J＝9.4,4.8,2.3Hz,4H),7.38-7.28(m,2H),7.10(t,J＝8.6Hz,2H),6.51(d,J＝16.0Hz,1H),2.48(s,3H)；13CNMR(126MHz,CDCl3)δ165.21,164.20,163.20,162.18,159.24,154.33,145.47,143.38,132.98,130.43,130.40,130.33,130.26,129.06,124.96,123.55,118.52,116.68,116.30,116.12,115.04,115.02,77.33,77.27,77.07,76.82,15.93；HRMS(ESI)[M+H]+calcd.forC20H14FNO4:352.0975；found:352.0982.
实施例14
实施例14提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物14的核磁、质谱数据如下：
(化合物14，C21H17NO5).Yield 68％；m.p.150-152℃；1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.83(d,J＝16.0Hz,1H),7.59-7.53(m,4H),7.37-7.30(m,2H),6.94-6.92(m,2H),6.45(d,J＝16.0Hz,1H),3.85(s,3H),2.48(s,3H)；13C NMR(126MHz,CDCl3)δ164.70,161.83,159.30,154.32,146.52,143.34,132.92,130.12,129.05,126.91,124.94,123.67,118.57,116.67,114.44,112.54,77.32,77.27,77.07,76.81,55.46,15.91；HRMS(ESI)[M+H]+calcd.for C21H17NO5:364.1178；found:364.1182.
实施例15
实施例15提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物15的核磁、质谱数据如下：
(化合物15，C20H14N2O6).Yield 70％；m.p.221-222℃；1H NMR(500MHz,Chloroform-d)δ8.30–8.27(m,2H),8.16(s,1H),7.91(d,J＝16.0Hz,1H),7.76-7.74(m,2H),7.60(ddd,J＝14.2,8.0,1.6Hz,2H),7.39-7.31(m,2H),6.73(d,J＝16.1Hz,1H),2.50(s,3H)；13C NMR(126MHz,CDCl3)δ163.40,162.80,159.19,154.37,148.78,143.74,143.51,140.12,133.13,129.09,128.95,125.02,124.29,123.35,119.71,118.46,116.75,77.30,77.25,77.05,76.79,16.02；HRMS(ESI)[M+H]+calcd.for C20H14N2O6:379.0923；found:379.0927.
实施例16
实施例16提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物16的核磁、质谱数据如下：
(化合物16，C21H14F3NO4).White sold；Yield 75％；m.p.169-171℃；1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.88(d,J＝16.1Hz,1H),7.71-7.65(m,4H),7.61-7.56(m,2H),7.37-7.30(m,2H),6.66(d,J＝16.1Hz,1H),2.49(s,3H)；13C NMR(126MHz,CDCl3)δ163.76,162.54,159.21,154.35,144.86,143.46,133.06,129.07,128.47,126.00,125.97,124.99,123.42,118.49,117.96,116.70,77.32,77.07,76.81,15.97；HRMS(ESI)[M+H]+calcd.for C21H14F3NO4:402.0944；found:402.0951.
实施例17
实施例17提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，化合物17的核磁、质谱数据如下：
(化合物18，C20H15NO5).Yield 75％；m.p.156-158℃；1H NMR(500MHz,DMSO-d6)δ10.12(d,J＝23.3Hz,1H),8.33(d,J＝23.1Hz,1H),7.93(d,J＝8.4Hz,1H),7.78-7.48(m,5H),6.83(d,J＝8.5Hz,2H),6.61(d,J＝16.0Hz,1H),2.37(s,4H)；13C NMR(126MHz,DMSO)δ164.49,162.21,160.73,159.15,154.18,146.98,143.66,133.60,131.22,130.00,125.51,125.44,123.73,118.89,116.68,116.30,116.26,111.91,40.56,40.47,40.39,40.30,40.22,40.13,40.06,39.97,39.89,39.80,39.63,39.46,16.12；HRMS(ESI)[M+H]+calcd.for C20H15NO5:350.1018；found:350.1025.
实施例18
实施例18提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物18的核磁、质谱数据如下：
(化合物18，C20H13ClBrNO4).Yield 70％；m.p.201-203℃；1H NMR(500MHz,Chloroform-d)δ8.12(s,1H),7.81(d,J＝16.0Hz,1H),7.57-7.53(m,2H),7.51(d,J＝8.3Hz,1H),7.47-7.43(m,2H),7.37(d,J＝1.9Hz,1H),7.30(dd,J＝8.4,2.0Hz,1H),6.57(d,J＝16.0Hz,1H),2.47(s,3H)；13C NMR(126MHz,CDCl3)δ164.00,161.98,158.54,154.54,145.53,142.56,139.10,133.00,132.30,129.81,129.70,125.68,125.24,123.42,117.09,117.08,115.88,77.31,77.26,77.05,76.80,15.87；HRMS(ESI)[M+H]+calcd.forC20H13ClBrNO4:483.9343；found:483.9348.
实施例19
实施例19提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物19的核磁、质谱数据如下：
(化合物19，C20H13Br2NO4).Yield 70％；m.p.190-191℃；1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),7.81(d,J＝16.0Hz,1H),7.58-7.53(m,3H),7.48-7.42(m,4H),6.57(d,J＝16.0Hz,1H),2.47(s,3H)；13C NMR(126MHz,CDCl3)δ164.00,162.00,158.48,154.44,145.56,142.65,132.99,132.31,129.89,129.71,128.52,127.21,125.25,123.68,120.05,117.43,115.86,77.30,77.25,77.05,76.80,15.88；HRMS(ESI)[M+H]+calcd.for C20H13Br2NO4:489.9282；found:489.9286.
实施例20
实施例20提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物20的核磁、质谱数据如下：
(化合物20，C20H13BrFNO4).Yield 70％；m.p.186-188℃；1H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.81(d,J＝16.0Hz,1H),7.56(dd,J＝7.0,5.0Hz,3H),7.46(d,J＝8.2Hz,2H),7.08(dt,J＝8.3,1.7Hz,2H),6.57(d,J＝16.0Hz,1H),2.47(s,3H)；13CNMR(126MHz,CDCl3)δ166.22,164.18,164.03,162.06,158.79,155.63,155.53,145.49,142.81,133.01,132.30,132.20,130.81,130.73,129.70,125.23,122.31,122.28,115.91,115.27,115.24,113.45,113.27,104.53,104.32,77.30,77.05,76.79,15.89；HRMS(ESI)[M+H]+calcd.for C20H13BrFNO4:430.0085；found:430.0085.
实施例21
实施例21提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物21的核磁、质谱数据如下：
(化合物21，C21H16BrNO4).Yield 70％；m.p.198-201℃；1H NMR(500MHz,Chloroform-d)δ8.14(s,1H),7.83(d,J＝16.0Hz,1H),7.59-7.55(m,2H),7.48-7.45(m,3H),7.20-7.13(m,2H),6.60(d,J＝16.0Hz,1H),2.50(s,6H)；13C NMR(126MHz,CDCl3)δ164.11,162.51,159.51,154.52,145.32,144.68,143.46,133.06,132.28,129.69,128.74,126.25,125.15,122.21,116.84,116.16,116.06,77.30,77.25,77.05,76.80,22.03,15.97；HRMS(ESI)[M+H]+calcd.for C21H16BrNO4:426.0336；found:426.0335.
实施例22
实施例22提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物22的核磁、质谱数据如下：
(化合物22，C21H16BrNO5).Yield 70％；m.p.205-210℃；1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),7.80(d,J＝16.0Hz,1H),7.57-7.53(m,2H),7.49-7.43(m,3H),6.88(dd,J＝8.6,2.4Hz,1H),6.83(d,J＝2.4Hz,1H),6.57(d,J＝16.0Hz,1H),3.90(s,3H),2.47(s,3H)；13C NMR(126MHz,CDCl3)δ164.16,163.91,162.61,159.61,156.44,145.25,143.58,133.08,132.27,130.14,129.68,125.13,119.67,116.12,113.44,112.20,100.53,77.30,77.25,77.05,76.79,55.93,15.93；HRMS(ESI)[M+H]+calcd.forC21H16BrNO5:442.0251；found:442.0285.
实施例23
实施例23提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物23的核磁、质谱数据如下：
(化合物23，C20H13ClBrNO4).Yield 70％；m.p.201-203℃；1H NMR(500MHz,Chloroform-d)δ8.06(s,1H),7.82(d,J＝16.0Hz,1H),7.58-7.53(m,5H),7.46(d,J＝8.2Hz,2H),7.33-7.30(m,1H),6.58(d,J＝16.0Hz,1H),2.47(s,3H)；13C NMR(126MHz,CDCl3)δ163.98,161.87,158.62,152.67,145.61,142.03,132.99,132.94,132.31,130.28,129.72,128.06,125.26,124.73,119.52,118.18,115.82,77.30,77.25,77.05,76.79,15.92；HRMS(ESI)[M+H]+calcd.for C20H13ClBrNO4:447.9771；found:447.9769.
实施例24
实施例24提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物24的核磁、质谱数据如下：
(实施例24，C20H13Br2NO4).Yield 65％；m.p.171-172℃；1H NMR(500MHz,Chloroform-d)δ8.08(s,1H),7.61-7.57(m,3H),7.55-7.51(m,3H),7.49-7.47(m,2H),6.60(d,J＝16.0Hz,1H),2.50(s,3H)；13C NMR(126MHz,CDCl3)δ164.00,161.85,158.57,153.14,145.62,141.94,135.74,132.99,132.31,131.13,129.72,125.26,124.69,120.01,118.45,117.55,115.82,77.30,77.25,77.04,76.86,76.79,15.92；HRMS(ESI)[M+H]+calcd.forC20H13Br2NO4:489.9282；found:489.9284.
实施例25
实施例25提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物25的核磁、质谱数据如下：
(化合物25，C20H13BrFNO4).Yield 65％；m.p.192-193℃；1H NMR(500MHz,Chloroform-d)δ8.08(s,1H),7.81(d,J＝15.9Hz,1H),7.55(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.37-7.29(m,2H),7.24(d,J＝2.9Hz,1H),6.57(d,J＝16.0Hz,1H),2.47(s,3H)；13C NMR(126MHz,CDCl3)δ163.98,161.95,159.87,158.83,157.92,150.50,150.48,145.57,142.32,142.30,132.99,132.30,129.71,125.25,124.70,120.64,120.44,119.23,119.16,118.38,118.32,115.84,114.19,114.00,77.31,77.26,77.05,76.80,15.91；HRMS(ESI)[M+H]+calcd.for C20H13BrFNO4:430.0089；found:430.0085.
实施例26
实施例26提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物26的核磁、质谱数据如下：
(化合物26，C21H16BrNO4).Yield 70％；m.p.182-183℃；1H NMR(500MHz,Chloroform-d)δ8.09(s,1H),7.85-7.78(m,1H),7.58-7.53(m,2H),7.48-7.43(m,2H),7.39(dd,J＝8.4,2.1Hz,1H),7.34(d,J＝2.1Hz,1H),7.25-7.21(m,1H),6.58(d,J＝16.0Hz,1H),2.47(s,3H),2.42(s,3H)；13C NMR(126MHz,CDCl3)δ164.12,162.47,159.48,152.52,145.39,143.43,134.76,134.14,133.05,132.29,129.70,128.70,125.17,123.33,118.27,116.41,116.01,77.30,77.25,77.05,76.79,20.82,15.99；HRMS(ESI)[M+H]+calcd.forC21H16BrNO4:426.0342；found:426.0335.
实施例27
实施例27提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例12，其区别在于，步骤S1中的化合物a的结构式为
其中，化合物27的核磁、质谱数据如下：
(化合物27，C21H16BrNO5).Yield 70％；m.p.251-253℃；1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),7.81(d,J＝16.0Hz,1H),7.56(d,J＝8.2Hz,2H),7.46(d,J＝8.2Hz,2H),7.29(d,J＝9.1Hz,1H),7.17(dd,J＝9.1,2.9Hz,1H),6.98(d,J＝2.9Hz,1H),6.58(d,J＝16.0Hz,1H),3.85(s,3H),2.48(s,3H)；13C NMR(126MHz,CDCl3)δ164.10,162.40,159.41,156.36,148.87,145.42,143.26,133.03,132.29,132.27,129.70,125.19,123.72,121.08,118.86,117.75,115.99,110.54,77.30,77.25,77.05,76.80,55.89,15.95；HRMS(ESI)[M+H]+calcd.for C21H16BrNO5:442.0251；found:442.0285.
对比例1
对比例1提供一种香豆素肟酯类化合物，其结构式如下：
制备方法同实施例1，其区别在于，步骤S3中的化合物b的结构式为
其中，对比例1的核磁、质谱数据如下：
(对比例1，C18H13NO4).Yield 72％；m.p.157-159℃；1H NMR(500MHz,Chloroform-d)δ8.20(s,1H),8.13(dd,J＝8.1,1.5Hz,2H),7.66-7.57(m,3H),7.51(t,J＝7.7Hz,2H),7.39-7.30(m,2H),2.55(s,3H)；13C NMR(126MHz,CDCl3)δ163.60,162.71,159.25,154.37,143.51,133.67,133.02,129.76,129.09,128.71,128.66,124.98,123.48,118.53,116.70,77.33,77.07,76.82,16.03；HRMS(ESI)[M+H]+calcd.for C18H13NO4:308.0914；found:308.0926.
实验例1
实施例1～27和对比例1的化合物对α-葡萄糖苷酶抑制活性测试，测试方法如下：
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度为0.05U/mL，并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为0.25mM的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL工作浓度为0.05U/mL的α-葡萄糖苷酶，130μL(pH6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例1中制备得到的吲哚酮类衍生物3a～3v)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)待测化合物的α-葡萄糖苷酶抑制活性根据如下公式计算：
抑制率(％)＝[(OD3-OD)-(OD1-OD)]/OD3-OD×100％
其中OD代表空白对照组的吸光度值，数据处理：使用MS Excel分析处理数据，并用Origin 9.1计算得到半数抑制浓度(IC50)，IC50代表在所述实验条件下，α-葡萄糖苷酶的活性被抑制50％时所需待测化合物的浓度。
3、结果分析
应用体外酶学实验对合成得到的化合物进行α-葡萄糖苷酶抑制活性评价，其测定结果如表1所示：
表1实施例1～27和对比例1对α-葡萄糖苷酶的体外抑制活性评价
| IC50(μM) | IC50(μM) | ||
| 实施例1 | 15.91±0.25 | 实施例16 | 19.66±0.04 |
| 实施例2 | 10.95±0.11 | 实施例17 | 21.54±0.02 |
| 实施例3 | 6.46±0.05 | 实施例18 | 3.42±0.07 |
| 实施例4 | 29.21±0.32 | 实施例19 | 2.54±0.04 |
| 实施例5 | 19.34±0.22 | 实施例20 | 3.92±0.02 |
| 实施例6 | 26.12±0.26 | 实施例21 | 5.24±0.16 |
| 实施例7 | 26.16±0.26 | 实施例22 | 6.43±0.06 |
| 实施例8 | 26.14±0.26 | 实施例23 | 4.25±0.02 |
| 实施例9 | 34.35±0.31 | 实施例24 | 3.81±0.14 |
| 实施例10 | 13.39±0.09 | 实施例25 | 3.73±0.10 |
| 实施例11 | 6.34±0.05 | 实施例26 | 6.17±0.04 |
| 实施例12 | 5.06±0.08 | 实施例27 | 7.84±0.14 |
| 实施例13 | 11.55±0.13 | 对比例1 | 93.23±0.25 |
| 实施例14 | 15.09±0.10 | 阿卡波糖 | 640.57±1.13 |
| 实施例15 | 8.71±0.21 | —— | —— |
实验例2
采用体外酶动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评价：
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别为0.0375U/mL、0.05U/mL、0.0625U/mL、0.075U/mL并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为0.25mM的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL浓度分别为0.0375U/mL、0.05U/mL、0.0625U/mL、0.075U/mL的α-葡萄糖苷酶，130μL(PH 6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例19的化合物19)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL浓度为0.25mM的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)数据处理：使用MS Excel分析处理数据，酶反应体系的反应速率为△OD/min。
3、结果分析
酶动力学抑制类型评价实验测定结果如图1所示。由图1可以看出，抑制剂以非共价键与酶结合阻遏酶的活性，是一种可逆抑制作用。
实验例3
采用体外底物动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评价：
1、试剂与标准溶液的配制
(1)100mM磷酸缓冲液(PBS，pH 6.8)：称取一定质量的磷酸二氢钾与磷酸氢二钠，用超纯水溶解，用于溶解稀释试剂。
(2)α-葡萄糖苷酶溶液配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度为0.05U/mL，并分装冷冻。
(3)底物配制：准确称取适量4-硝基苯基-D-吡喃葡糖苷(PNPG)，加入100mM PBS溶液溶解，配制成浓度为(0.25mM、0.5mM、0.75mM、1mM)的底物工作液，涡旋混匀，每次实验前新鲜配制。
供试药物配制:准确称取待测药物适量，用DMSO溶解配制为10mM的储备液，于-20℃避光保存。实验前用DMSO稀释至不同所需浓度(0～200μM)，DMSO含量等于5％。
2、实验步骤
(1)在96孔板上依次加入10μL浓度为0.5U/mL的α-葡萄糖苷酶，130μL(pH 6.8)浓度为100mM的磷酸缓冲液，10μL不同浓度的化合物(实施例19的化合物19)，空白对照组用10μL含量等于5％的DMSO来替换10μL化合物，用阿卡波糖作为阳性对照，每组平行设置4个复孔，将酶反应体系置于酶标仪上37℃孵育10min。
(2)随后，向酶反应体系中加入50μL不同浓度的底物PNPG以启动酶反应，将微孔板置于酶标仪上37℃继续孵育15min，在孵育的过程中平均分配3次时间，每段时间于波长405nm读数一次，读数记为OD1、OD2、OD3。
(3)数据处理：使用MS Excel分析处理数据，酶反应体系的反应速率为△OD/min。
3、结果分析
底物动力学抑制类型评价实验测定结果如图2所示，图2对应化合物19的在体外对α-葡萄糖苷酶的底物动力学图，图2中的(a)为双倒数作图法作出的底物动力学图，(b)为截距图。由图2可以看出，筛选得到的抑制剂为非竞争性抑制剂。表明它只与α-葡萄糖苷酶结合。同时，根据图2可以得知，化合物19抑制常数KI为1.5。
实验例4
采用分子对接(Molecular docking)的方法分析活性实施例19中制备的化合物19与α-葡萄糖苷酶的相互作用规律：
通过分子对接分析化合物19与α-葡萄糖苷酶的结合方式。化合物19和α-葡萄糖苷酶之间的对接结果如图3所示。化合物19以“U形”构象很好地位于活性部位，肉桂酸部分嵌套在活性部位内(图3a～c)。详细的交互结果分别使用3D视图(图3c)和2D视图(图3d)显示。观察到香豆素的羰基和肟的氮分别与Arg312形成氢键(键长：和/>)，这被认为是化合物19和α-葡萄糖苷酶之间的关键相互作用。溴香豆素片段与Phe157/>和Pi-烷基相互作用His239和His279形成Pi-Pi堆积。此外，溴肉桂酰基与Tyr71形成Pi烷基相互作用。所有这些相互作用都有助于化合物19锚定在α-葡萄糖苷酶的活性部位。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。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，均应包含在本发明权利要求的保护范围之内。
Claims (8)
1.一种香豆素肟酯类化合物或其药学上可接受的盐，其特征在于，所述香豆素肟酯类化合物具有如式I所示的结构：
R2和R3独立地选自H、卤素、C1～10的烷基、C1～10的烷氧基；
所述R1选自被溴、羟基或卤代烷基取代的苯基、未取代的苯乙烯基、被烷基、卤素、硝基、羟基、烷氧基或卤代烷基取代的苯乙烯基。
2.一种香豆素肟酯类化合物或其药学上可接受的盐，其特征在于，所述香豆素肟酯类化合物选自如下结构中的一种：
3.根据权利要求1或2所述的香豆素肟酯类化合物或其药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
S1、将化合物a与乙酰乙酸乙酯进行Perkin反应，得到中间体1；
S2、将所述中间体1与盐酸羟胺进行反应，得到中间体2；
S3、将所述中间体2与化合物b进行酯化反应得到式I所示的香豆素肟酯类化合物；
其中，所述化合物a、中间体1、中间体2、化合物b的结构式如下：
4.根据权利要求3所述的香豆素肟酯类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S1中，所述化合物a与所述乙酰乙酸乙酯的摩尔比为1：(1.1～2)。
5.根据权利要求3所述的香豆素肟酯类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2中，所述中间体1和所述盐酸羟胺的摩尔比为1：(2.5～3.0)。
6.根据权利要求3所述的香豆素肟酯类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S3中，所述中间体2和所述化合物b的摩尔比为1：(1.2～1.5)。
7.一种药物组合物，其特征在于，包含权利要求1或2所述的香豆素肟酯类化合物或其药学上可接受的盐，及其药学上可接受的辅料。
8.根据权利要求1或2所述的香豆素肟酯类化合物或其药学上可接受的盐或权利要求7所述的药物组合物在制备预防和/或治疗糖尿病的药物中的应用。
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