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CN104829569B - 一种2‑苯基‑苯骈五元杂环类化合物及其衍生物的应用 - Google Patents

一种2‑苯基‑苯骈五元杂环类化合物及其衍生物的应用 Download PDF

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CN104829569B
CN104829569B CN201510238646.8A CN201510238646A CN104829569B CN 104829569 B CN104829569 B CN 104829569B CN 201510238646 A CN201510238646 A CN 201510238646A CN 104829569 B CN104829569 B CN 104829569B
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周欣欣
崔露
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Guangzhou University of Chinese Medicine
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Abstract

本发明公开一种2‑苯基‑苯骈五元杂环类化合物、其药学上可接受的盐或酯及其衍生物作为乙酰胆碱酯酶抑制剂的应用。所述2‑苯基‑苯骈五元杂环类化合物的结构式如式（II）所示：其中，R1为氧、氮或硫；R2为氢、羰基或烷基；R3为氢；R4为氢、异丙基或取代氨基；R5为氢或亚硝酸基；R6为氢或异丙基；R7为氢或酯基；R8为氢；R9为氢、烷氧基、取代氨基、苯基或烷基；R10为氢、烷氧基或亚硝酸基；R11为氢、酯基或烷氧基；R12为氢或烷基；R13为氢或烷基。该类化合物显示出高的乙酰胆碱酯酶抑制活性，为新药开发提供方向。

Description

一种2-苯基-苯骈五元杂环类化合物及其衍生物的应用
技术领域
本发明属于医药技术领域。更具体地，涉及一种2-苯基-苯骈五元杂环类化合物及其衍生物的医药应用。
背景技术
乙酰胆碱酯酶（acetylcholine esterase，AChE），是一种降解（通过其水解活性）神经递质乙酰胆碱成为胆碱和乙酸的酶。该酶主要存在于神经肌肉接头与胆碱能神经系统中，在这些地方该酶的活性就是为了终止突触传递。AChE具有极高的水解活性，每秒钟一分子的乙酰胆碱酯酶可以水解25000分子的乙酰胆碱。经AChE作用而产生的胆碱通过重摄取被转运进入神经末梢，在那里被重新利用以合成新的乙酰胆碱分子。
研究显示，与乙酰胆碱酯酶相关的疾病有很多，如重症肌无力疾病，AChE抑制剂就是治疗该病的重要药物，它可以抑制乙酰胆碱酯酶的活性，减缓乙酰胆碱的水解，从而使得乙酰胆碱与受体充分结合弥补受体遭到破坏的缺陷，从达到神经冲动的阈值，改善疾病状况。另外，AChE抑制剂也是治疗老年痴呆的一类药物。因此，乙酰胆碱酯酶抑制剂（AChE抑制剂）的研究有着重要的意义。
目前已知的，乙酰胆碱酯酶抑制剂有石杉碱类化合物、加兰它敏、毒扁豆碱、他克林类、哌啶类等。
发明内容
本发明要解决的技术问题是克服现有乙酰胆碱酯酶抑制剂的不足，提供一种新的AChE抑制剂，为AChE抑制剂新药开发提供方向，用于治疗相关的疾病（如：重症肌无力，青光眼，老年痴呆等）。
本发明的目的是提供一种2-苯基-苯骈五元杂环类化合物及其衍生物的医药应用。
本发明上述目的通过以下技术方案实现：
一种2-苯基-苯骈五元杂环类化合物、其药学上可接受的盐或酯及其衍生物作为乙酰胆碱酯酶抑制剂的应用。所述2-苯基-苯骈五元杂环类化合物的结构式如式（II）所示：
其中，R1为氧、氮或硫；R2为氢、羰基或烷基； R3为氢；R4为氢、异丙基或取代氨基；R5为氢或亚硝酸基； R6 为氢或异丙基； R7 为氢或酯基；R8为氢； R9为氢、烷氧基、取代氨基、苯基或烷基； R10为氢、烷氧基或亚硝酸基 ；R11为氢、酯基或烷氧基； R12为氢或烷基；R13为氢或烷基。
优选地，R1为氧；R2为氢；R3 为氢；R4为取代氨基，异丙基；R5 为氢、；R6为氢，异丙基；R7为氢；R8为氢；R9为苯基；R10为氢；R11为烷氧基；R12为氢；R13为氢。
所述药学上可接受的盐为式（II）所示化合物与酸或碱形成的药学上可接受的盐。
更优选地，所述2-苯基-苯骈五元杂环类化合物的结构式如X19或X21所示：
上述化合物可用于制备乙酰胆碱酯酶抑制剂药物。
包含有效量的式（II）所示化合物的能够抑制乙酰胆碱酯酶的药物或药物组合物也在本发明的保护范围之内。
另外，式（II）所示化合物在制备治疗乙酰胆碱酯酶相关疾病的药物中的应用。所述乙酰胆碱酯酶相关疾病为可以通过抑制乙酰胆碱酯酶进行治疗的疾病。
优选地，所述乙酰胆碱酯酶相关疾病为重症肌无力、青光眼或老年痴呆。
本发明的目的是从传统的中药处方中结合虚拟筛选的方法，发现一类新型的乙酰胆碱酯酶抑制剂。补中益气汤改良方源于补中益气汤，鉴于以上基础，我们以乙酰胆碱酯酶为靶标，结合虚拟筛选和实验方法，从补中益气汤改良方中发现抑制乙酰胆碱酯酶的活性物质。我们对该处方9种草药按君臣佐使的方法建立四个分子数据库，与从BingingDatabase 收集AChE抑制剂（IC50<=10000nM）进行二维和三维相似度的计算，结合分子对接研究，结果表明2-苯基-苯骈五元杂环类是抑制AChE起效的一类关键骨架结构。
然后，我们基于2-苯基-苯骈五元杂环类进行数据库搜寻，找出含有该母核的化合物，最终选取24个化合物。然后对选取的24个化合物进行乙酰胆碱酯酶活性实验（Ellmanassay）。酶活性实验表明绝大多数均对乙酰胆碱酯酶具有抑制活性，其中5个化合物显示出很高的活性（10μM的单点抑制率大于50%，最高达84%）。
同时，本发明也启发了我们可以从传统中医药处方出发，用数据挖掘结合计算的方法发现活性化合物，开发新药。
本发明具有以下有益效果：
本发明从传统中药处方角度出发，发现了新药开发的新骨架，提供了一类新的乙酰胆碱酯酶的抑制剂，即2-苯基-苯骈五元杂环类化合物，它们作为抑制AChE的化合物，与上市药物多奈哌齐（Donepezil）相比，表现出更高的AChE抑制活性。
该类化合物可为研发新的AChE抑制剂新药提供方向，为重症肌无力或老年痴呆等相关疾病的治疗或预防新药的开发提供方向。
而且本发明提供的2-苯基-苯骈五元杂环类化合物结构简单、易合成，易于推广应用。
附图说明
图1为阳性对照多奈哌齐（Donepezil）的化学结构式。
图2为化合物X4 化合物的量效曲线的图。
图3为化合物X10化合物的量效曲线的图。
图4为化合物X11化合物的量效曲线的图。
图5为化合物X19化合物的量效曲线的图。
图6为化合物X21化合物的量效曲线的图。
图7为化合物Donepezil的量效曲线的图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1 2-苯基-苯骈五元杂环类化合物的虚拟筛选
1、TCM数据库和AChE抑制剂数据的建立
（1）针对邓老的补中益气汤改良方，通过中国传统医学系统药理学数据库和文献找出君臣佐使的化合物，建立了4个TCM数据库。
（2）从Binding database 中收集乙酰胆碱酯酶抑制剂（IC50<=10000nM），建立AChE抑制剂的数据库。
2、化合物TCM数据库预处理
虚拟筛选化合物库为自备化合物数据库。化合物库作如下处理：去除离子及络合水分子、加电荷、质子化、产生三维构象。这些流程均在药物设计软件包MOE 2010中完成。其中质子化在pH6.5～8.5条件下进行。
准备好的数据库用于虚拟筛选。
3、用“Role of five”的方法，去掉不适合作为药物的分子。将TCM数据库与AChE抑制剂的数据库进行二维和三维相似度的计算，结合分子对接研究，寻找候选活性化合物，进行骨架分类，结果表明，2-苯基-苯骈五元杂环类结构是抑制AChE起效的一类关键骨架结构。
4、然后，基于2-苯基-苯骈五元杂环类结构进行子结构匹配的数据库搜寻，找出含有该母核的化合物。最终得到24个2-苯基-苯骈五元杂环类化合物，分别记作X1～X24。各自的结构式如下所示：
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实施例2 Ellman实验
1、对实施例1得到的24个化合物进行乙酰胆碱酯酶活性实验（Ellman assay）
化合物用反应缓冲液稀释（磷酸盐缓冲液，0.08M Na2HPO4和0.02M NaH2PO4，pH8.0），0.057 U/mL的hAChE同化合物在37 ℃ 孵育15分钟，后加入显色液DTNB，至终浓度50μM，再与终浓度50μM的底物硫代乙酰胆碱混合后，立即在412nm波长检测吸光度值，一分钟间隔连续取五次值，求每分钟变化值的平均值。抑制率为加药组与非加药组的比值，多奈哌齐(Donepezil) 作为阳性对照。
按照公式：抑制率（%）=（1-加药组每分钟吸光度变化值/无药组每分钟吸光度变化值）*100%。
每次取前五分钟的平均值，重复三次，计算标准差，计算各化合物不同浓度下的半数抑制浓度（IC50）。
2、结果
（1）酶活性实验结果如表1所示。
表1 筛选24个化合物的结构及活性数据
表1数据表明，24个化合物中绝大多数均对乙酰胆碱酯酶具有抑制活性，其中X4、X10、X11、X19和X21这5个化合物显示出很高的活性（10μM的单点抑制率大于50%，最高达84%。
（2）另外，测出X4、X10、X11、X19和X21这5个活性化合物的IC50（半数抑制浓度）如表2所示：
表2
。

Claims (4)

1.一种2-苯基-苯骈五元杂环类化合物在制备乙酰胆碱酯酶抑制剂药物中的应用，其特征在于，所述2-苯基-苯骈五元杂环类化合物的结构式如X19或X21所示：
。
2.权利要求1中X19或X21所示化合物在制备治疗乙酰胆碱酯酶相关疾病的药物中的应用。
3.根据权利要求2所述应用，其特征在于，所述乙酰胆碱酯酶相关疾病为可以通过抑制乙酰胆碱酯酶进行治疗的疾病。
4.根据权利要求2所述应用，其特征在于，所述乙酰胆碱酯酶相关疾病为重症肌无力、青光眼或老年痴呆。
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