CN103570711B - 一种咯萘啶类化合物及其用途 - Google Patents
一种咯萘啶类化合物及其用途 Download PDFInfo
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- CN103570711B CN103570711B CN201210258442.7A CN201210258442A CN103570711B CN 103570711 B CN103570711 B CN 103570711B CN 201210258442 A CN201210258442 A CN 201210258442A CN 103570711 B CN103570711 B CN 103570711B
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- pyronaridine
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种咯萘啶类化合物，其结构通式如下式I所示，其中R1、R2、R3和R4是作用位点，使得该类化合物具有抑制疟原虫体内PDE的活性。咯萘啶类化合物的结合自由能低于咯萘啶，使得该咯萘啶类化合物有比咯萘啶更高的抑制疟原虫体内PDE的活性，因此具有更强的抗疟活性。
Description
技术领域
本发明涉及一种咯萘啶类化合物及其用途，特别是涉及一种通过对咯萘啶的结构优化使其具有更低的结合自由能、更高的抑制疟原虫体内PDE（磷酸二酯酶）活性的抗疟的咯萘啶类化合物。
背景技术
咯萘啶（pyronaridine，PYR）是1970年我国创制的疟原虫红内期无性体杀灭剂，代号7351。其相应药物的化学名为2-甲氧基-7-氯-10-[3′,5'-双（吡咯烷基-1-甲基）-4'-羟基-苯基]氨基苯并[b]1,5-萘啶四磷酸盐，商品名为疟乃停（malaridine），分子式为：
PYR能有效的作用于恶性疟原虫，红内期原虫不同发育阶段对咯萘啶的敏感顺序为环状体>滋养体>裂殖体，并且对于各期原虫的作用咯萘啶均大于氯喹。
咯萘啶对氯喹、奎宁及乙胺嘧啶或甲氟喹等抗性株均未呈现交叉抗性。用体外测试法测得咯萘啶对我国恶性疟原虫敏感株FCC-102/JS的IC50为15.4±2.50nM，而对恶性疟原虫抗氯喹株FCC-4/HN则为15.0±1.4nM，表明咯萘啶与氯喹无交叉抗性；泰国东部对氯喹、奎宁及乙胺嘧啶有抗性的疟原虫分离物，体外测试结果发现其对咯萘啶仍敏感，半数抑制浓度（IC50）为8.40nM，最小抑制浓度（MIC）为21.5nM，而对泰国北部药物较敏感的恶性疟原虫分离物测得的IC50为10.1nM，MIC为26.8nM，这表明咯萘啶对泰国不同地区的恶性疟原虫分离物同样敏感；在甲氟喹及恩哌罗林（enpiroline）治疗失败的病例中获得的恶性疟原虫分离物，测得IC50为8.9nM，MIC为18.8nM，表明咯萘啶（PYR）对甲氟喹未产生交叉抗性。
然而咯萘啶的具体作用和机制至今仍未明确。对伯氏疟原虫体内实验及恶性疟原虫体外实验表明它首先是破坏疟原虫滋养体的复合膜结构功能以及食物泡的代谢活力，并呈现进行性加重而迅速杀虫，同时，还发现了线粒体、内质网、核膜、核糖体及染色质等的变化。而对于咯萘啶的作用靶标，科学家们也进行了不少研究。Chavalitshewinkoon的研究表明，咯萘啶作用于DNA拓扑异构酶II（Chavalitshewinkoon,P.,Wilairat,P.,Gamage,S.,Denny,W,Figgitt,D.,Ralph,R.,1993.Structure-activity），但是更多的研究结果显示咯萘啶不参与蛋白质-DNA复合物的形成，从而认为DNA拓扑异构酶II并不是咯萘啶的作用位点。此后，基于咯萘啶与氯喹的相似结构，Auparakkitanon发现这两种药物均能抑制β-血红素的生成并且形成药物-血红素复合物，最终抑制依赖GSH的血红素降解，加速血红素诱导的血红细胞降解过程，β-血红素被认为是咯萘啶的作用靶标（Auparakkitanon,S.,Chapoomram,S.,Kuaha,K.,Chirachariyavej,T.,Wilairat,P.,2006.Targetingofhematinbytheantimalarialpyronaridine.AntimicrobAgentsChemother50,2197-2200.）。但是与氯喹不同，在同样条件下，所需的咯萘啶药物浓度仅为氯喹的1/100，而且它与哌喹、羟基哌喹及氯喹等均无明显的交叉抗性，这些事实提示了咯萘啶可能还存在其他的作用位点或作用途径，因此该问题还值得进一步研究证明。
本发明中，发明人根据咯萘啶的新的作用机制，解释了咯萘啶与氯喹不同的抗疟原理，并以此鉴于咯萘啶与PDE的结合模式，发明人又基于咯萘啶的结构进行了优化，得到的化合物显示出与PDE有更低的结合自由能，提示具有更强的结合作用，因此，进一步开发了活性更强的抗疟药物。
发明内容
本发明证实了咯萘啶存在现在未知的作用位点和作用途径，发现了新的作用机理，即咯萘啶是PDE的抑制剂。并且通过对咯萘啶的上述位点的结构修饰使其对PDE具有较低的结合自由能，结构改进的咯萘啶、即如下通式I所示的咯萘啶类化合物具有可能的抑制疟原虫体内PDE（磷酸二酯酶）活性的机理，这是一种咯萘啶类化合物的抗疟作用新机制。同时通过化学合成以及体内活性测试验证了咯萘啶类化合物具有良好的抗疟效果。
因此，本发明的一个目的是提供一种如下通式I所示的咯萘啶类化合物及其药学上可接受的盐。
本发明的另一目的是提供所述如下通式I所示的咯萘啶类化合物及其药学上可接受的盐的用途。
本发明提供的一种咯萘啶类化合物及其药学上可接受的盐，其特征在于，其结构通式如下式I所示：
其中，R1是具有氢键受体位点、同时具有部分疏水能力的基团；R2是具有疏水能力、并且具有氢键受体性质的基团；而R3、R4是以疏水性质为主的基团。上述化合物具有可能的抑制疟原虫体内PDE的活性。
优选地，R1选自以下结构中：H、Cl、
X为F、Cl、Br或NH2；
Y为-CH3、-CH2CH3、-CH2CH2CH3或(CH3)2CH-；
R2选自以下结构中：H、
R3选自以下结构中：
R4选自以下结构中：
其中，R1，R2，R3，R4不能同时为：Cl，H，
以及
具体而言，本发明的咯萘啶类化合物可选自以下化合物中：
本发明所述“其药学上可接受的盐”是指，通式I所示的咯萘啶类化合物与无机酸或有机酸反应形成的常规的盐。例如，所述常规的盐可通过通式(I)化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(I)化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(I)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
一种包含如通式I所示的咯萘啶类化合物药物组合物，该药物组合物包括作为药物活性成分的如通式I所示的咯萘啶类化合物以及药学上可接受的各种辅剂。
所述通式I所示的咯萘啶类化合物对PDE的结合自由能低于咯萘啶，从而使得所述通式I所示的咯萘啶类化合物有比咯萘啶更高的抗疟活性。特别是，上述通式I所示的咯萘啶类化合物不仅是所述哺乳动物PDE4和PDE5的双重抑制剂，同时还极可能是以上所述疟原虫体内PDE（PfPDE）的抑制剂。
附图说明
图1A表明PYR在CHO-hbeta3AR细胞株上与异丙肾上腺素（ISO）的协同作用。
图1B表明PYR在CHO-pCDNA3.1细胞株上与福斯高林（FSK）的协同作用。
图2A表明PDE4阳性抑制剂咯利普兰（Rolipram）以及PYR对PDE4的抑制作用，IC50值分别为83.0nM和14.1μM。
图2B表明PDE5阳性抑制剂西地那非（Sildenafil）以及PYR对PDE5的抑制作用，IC50值分别为67.1nM和24.1μM。
图3A是PYR与PDE4的结合模式图。其中圆点为Mg离子与Zn离子；虚线代表氢键作用。
图3B是PYR与PDE5的结合模式图。其中圆点为Mg离子与Zn离子；虚线代表氢键作用。
具体实施方式
下面将参考附图描述本发明示范性的实施方式，以帮助理解本发明。以下实施方式只以举例的方式描述本发明。很明显，本领域普通技术人员可在本发明的范围和实质内，对本发明进行各种变通和修改。需要了解的是，本发明意欲涵盖在所附权利要求书中包括的变通和修改。
材料和仪器：
细胞培养用Ham'sF12培养基、G418抗生素、载体pCDNA3.1+购自Invitrogen；胎牛血清FBS购自hyclone公司；CHO-K1和HEK-293细胞来源于ATCC；pCDNA-beta3AR质粒购自MissouriS&TcDNAResourceCenter(Rolla,MO,USA)；pCRE-Luc质粒购自Stratagene；CHO-hbeta3AR以及CHO-pCDNA3.1稳转细胞株发明人自建；化合物Isoproterenolhydrochloride（ISO，异丙肾上腺素）购自TocrisBioscience公司;Forskolin（FSK，福斯高林）购自Sigma；Pyronaridine（咯萘啶）以及氯喹购买与东方公司；Rolipram受赠于上海药物研究所沈敬山教授实验室；Steady-GloLuciferase检测试剂购自Promega；转染试剂FUGENE6购自Roche公司；QIAGEN质粒抽提试剂盒购自QIAGEN公司；多功能酶标仪Flaxstation3购于MolecularDevices公司。所有的溶剂都重新蒸馏并经分子筛干燥。实验测试仪器AM-400（Bruker）核磁共振仪，HP5989A质谱仪，AllVarianCary100紫外光谱仪；B-540熔点仪。
实验实施例
咯萘啶(PYR)在CHO-hbeta3AR细胞上能与其阳性激动剂异丙肾上腺素（ISO）产生协同作用，同时在CHO-pCDNA3.1细胞上与阳性化合物福斯高林（Forskolin，FSK）也能产生协同作用，但作用机制不清。为了寻找咯萘啶（PYR）的潜在作用靶标，应用反向对接软件TarFisDock寻找其潜在作用靶标蛋白。根据对接结果，对打分排名靠前的10%的靶标进行了分析，预测PDE是PYR的潜在靶标，经实验验证发现咯萘啶（PYR）是哺乳动物PDE4和PDE5的双重抑制剂，IC50值分别为14.1μM和24.1μM。
根据序列分析，发现PDE的各个种属之间的催化核心区域很保守。因此，哺乳动物PDE的抑制剂对疟原虫应有抑制作用。哺乳动物PDE5的抑制剂扎普司特（Zaprinast）便是一个很好的例子，它在PfPDE（PlasmodiumfalciparumPDEs，恶性疟原虫PDE）上表现出抑制活性，同时也能抑制疟原虫的生长。特别是2011年《药物化学杂志》上发表了基于PDE5抑制剂进行结构改造从而发现了抗疟活性更强的化合物的报道。这些结果预示着咯萘啶（PYR）的抗疟效果极可能是通过对疟原虫PDE的抑制来实现的。
本发明通过用计算机分子模拟的方法找到了一系列结合自由能低于咯萘啶（PYR）本身的化合物，最后化学合成和体内抗疟活性实验验证了这些化合物具有更强的PDE抑制活性。
化学合成部分实施例：
通式I中的化合物合成路线如下：
（a）首先将正戊醇与新蒸馏的5-氨基-2-甲氧基吡啶，取代的邻氯苯甲酸化合物（1）及碳酸钾混合，于油浴上加热回流，将反应液进行水蒸汽蒸馏，残液冷却后过滤，收集沉淀，用95%乙醇洗涤数次，得到化合物（2）；
（b）将化合物（2）和三氯氧磷混合，于油浴上加热回流，减压蒸去未作用的三氯氧磷，残液慢慢倒入碎冰中，充分搅拌，用氨水中和到中性，放置过夜，过滤，收集沉淀，用丙酮洗涤数次，干燥，用氯仿重结晶，得到淡黄色针状结晶化合物（3）；
（c）将对氨基苯酚及研细的化合物（3）加入水和浓硫酸中加热至沸腾，加以搅动，点板跟踪至化合物（3）反应完全，趁热过滤，沉淀用稀氨水洗涤，再用冷水洗涤，最后用少量95%乙醇洗涤，干燥得到橘红色结晶固体化合物（4）；
（d）将化合物（4）和甲醛溶液及相应的吡咯衍生物于95%的乙醇中回流加热，趁热过滤，滤液放置冷却，析出结晶，收集晶体，用丙酮重结晶，得到目标产物，即通式I中的化合物。
具体反应式如下：
上述制备反应步骤均采用现有技术中本领域技术人员熟知的方法，对各个步骤的反应参数没有特别限制。本领域技术人员可以根据不同的最终预期的化合物，对上述反应式中涉及的各步骤反应的反应物、反应条件等适当作出调整。
根据上述本发明的通式I表示的化合物的合成方法，按照以下步骤的反应式2分别合成化合物PYR_90、PYR_98和PYR_99。
反应式2：
(a)首先取300毫升水和12毫升浓硫酸，再加入12克对氨基苯酚及研细的27.8克2-甲氧基-7,10-二氯胺基苯并[b]-1,5-萘啶（化合物1）加热至沸腾，加以搅动，点板跟踪至2-甲氧基-7,10-二氯胺基苯并[b]-1,5-萘啶反应完全，趁热过滤，沉淀用稀氨水洗涤，再用冷水洗涤，最后用少量95%乙醇洗涤，干燥得到橘红色结晶固体（化合物2），重32克，收率91.1%，熔点：268-270℃，1H-NMR((CD3)2SO)δ:10.01(s,1H,OH),9.60(s,1H,Ar-NH),8.24-6.79(m,9H,Ar-H),3.96(s,3H,OCH3);LC-MS:C19H14ClN3O2[M+1]+352.28.
实施例12-甲氧基-7-氯-10-(3’,5’-双3”-甲基四氢吡咯次甲基-4’-羟苯基)胺基苯并[b]-1,5-萘啶的制备（化合物PYR_90）
将0.003摩尔的2-甲氧基-7-氯-10-(4’-羟苯基)胺基苯并[b]-1,5-萘啶和5毫升甲醛溶液及0.008摩尔的3-甲基吡咯于10毫升95%的乙醇中回流加热6小时，趁热过滤，滤液放置冷却，析出结晶，收集晶体，用丙酮重结晶，重0.99克，收率60.4%，熔点168-170℃,1H-NMR((CD3)2SO)δ:9.05(s,1H,Ar-NH),8.21-6.71(m,7H,Ar-H),4.04(s,3H,OCH3)，3.36（s,4H,Ar-CH 2 N）,2.86(m,2H,N(CH 2 CH2CHCH2)CH3),2.50(m,2H,N(CH2CH2CHCH 2 )CH3),2.16(m,2H,N(CH 2 CH2CHCH2)CH3),1.94(m,2H,N(CH2CH2CHCH 2 )CH3),1.67(m,4H,N(CH2 CH 2 CHCH2)CH 3 ),1.60(m,2H,N(CH2CH2 CHCH2)CH3),1.05(d,6H,N(CH2CH2CH)2 CH 3 );LC-MS:C31H36ClN5O2[M+1]+546.20
实施例22-甲氧基-7-氯-10-(3’,5’-双六氢哌啶次甲基-4’-羟苯基)胺基苯并[b]-1,5-萘啶的制备（化合物PYR_98）
除了采用哌啶代替3-甲基吡咯以外，按照实施例1中相似的合成路线合成化合物2-甲氧基-7-氯-10-(3’,5’-双六氢哌啶次甲基-4’-羟苯基)胺基苯并[b]-1,5-萘啶（化合物PYR98），收率53.4%，熔点165-166℃1H-NMR((CD3)2SO)δ:9.02(s,1H,Ar-NH),8.20-6.81(m,7H,Ar-H),4.04(s,3H,OCH3)，3.38（s,4H,Ar-CH 2 N),2.86(m,8H,N(CH 2 CH2CH2CH2 CH 2 )),1.92(m,8H,N(CH2 CH 2 CH2 CH 2 CH2)),1.57(m,4H,N(CH 2 CH2CH2CH2CH2));LC-MS:C31H36ClN5O2[M+1]+546.20
实施例32-甲氧基-7-氯-10-(3’,5’-双4’’-甲基六氢哌啶次甲基-4’-羟苯基)胺基苯并[b]-1,5-萘啶的制备（化合物PYR_99）
除了采用4-甲基哌啶代替3-甲基吡咯以外，按照实施例1中相似的合成路线合成化合物2-甲氧基-7-氯-10-(3’,5’-双4”-甲基六氢哌啶次甲基-4’-羟苯基)胺基苯并[b]-1,5-萘啶的制备（化合物PYR99），收率60.4%，熔点172-174℃1H-NMR((CD3)2SO)δ:9.05(s,1H,Ar-NH),8.21-6.71(m,7H,Ar-H),4.04(s,3H,OCH3)，3.36（s,4H,Ar-CH 2 N）,2.86(m,8H,N(CH 2 CH2CHCH2 CH 2 )CH3),1.94(m,8H,N(CH2 CH 2 CHCH 2 CH2)CH3),1.60(m,2H,N(CH2CH2 CHCH2CH2)CH3),1.00(d,6H,N(CH2CH2CHCH2CH2 )CH 3 );LC-MS:C33H40ClN5O2[M+1]+574.15
生物活性测试实验实施例：
实验实施例1：咯萘啶在CHO-hbeta3AR和CHO-pCDNA3.1稳定细胞株上的协同作用
[试剂]
F12培养基，G418抗生素购自Invitrogen公司；胎牛血清（FBS）购于Hyclone；磷酸咯萘啶（PYR）标准品购自上海东方药品科技有限公司，用PBS缓冲液溶解；CHO-hbeta3AR以及CHO-pCDNA3.1稳定细胞株建于本实验室；异丙肾上腺素（Isoproterenol，ISO)购自TocrisBioscience；Forskolin（FSK）购买于Sigma；Steady-Glo荧光素酶检测试剂购于Promega；化学发光在Flaxstation3多功能酶标仪上检测。
[方法与结果]
CHO-hbeta3AR以及CHO-pCDNA3.1稳定细胞株在F12培养基（含10%FBS，500ng/μl的G418抗生素）中37℃，5%CO2的培养箱中培养。实验的前一天将细胞以30,000每孔的密度接到96孔板中，24小时后每孔加入100μl含有10μM（终浓度）PYR的不同浓度的ISO(CHO-pCDNA3.1细胞加的阳性药是不同浓度的FSK)，然后在37℃细胞培养箱中继续孵育3小时。3小时后，去掉96孔板中全部培养基，每孔加入一定量的Steady-Glo检测试剂，最后在Flaxstation3多功能酶标仪上检测化学发光。
如图1A和图1B所示，咯萘啶（PYR）在CHO-hbeta3AR以及CHO-pCDNA3.1细胞株上都能与阳性化合物分别产生协同作用，该协同作用不是通过受体，而可能是通过与调节cAMP有关的靶点起作用。
因此，证明咯萘啶（PYR）可通过作用于信号通路的某些靶点对胞内的cAMP水平进行调节。
实验实施例2：通过反对接程序TarFisDock寻找PYR的潜在靶点
[方法与结果]
为了寻找咯萘啶（PYR）在信号通路上的潜在靶标，通过反对接程序TarFisDock搜索潜在药物靶标数据库PDTD，该库拥有840个已知的药物靶标，结果取打分靠前的10%的靶标进行分析。经过分析，排名第47位的PDE4d可能是咯萘啶（PYR）的潜在靶标，因为PDE在调节细胞的cAMP以及cGMP作用中发挥着很重要的功能。
实验实施例3：咯萘啶（PYR）对PDE的抑制活性体外测试
[方法与结果]
为了验证PDE是咯萘啶（PYR）的潜在靶标，发明人进行了PDE的体外活性实验，包括PDE4以及PDE其他亚型的抑制活性检测。
步骤一：酶的分离
参照文献(Lanteretal.,2004)中的方法，分别从大鼠脑组织、大鼠肾脏、兔血小板、大鼠肾脏、大鼠血小板和牛视网膜中分离得到PDE1、PDE2、PDE3、PDE4、PDE5和PDE6。
分离按以下步骤进行：取动物组织经适当处理后，在含有20mMHEPES（pH7.2），0.25M蔗糖，1mMEDTA，1mM苯甲磺酰氟缓冲液中0℃匀浆，得到的匀浆在4℃低温离心机中以100，000g离心60分钟，上清液经孔径0.2微米的滤膜过滤，上样到预先以20mMHEPES,1mMEDTA和0.5mMPMSF的缓冲液平衡好的Mono-Q阴离子交换柱上，用0-1M的NaCl缓冲液梯度洗脱，流速1.5mL/min，将杂蛋白冲洗掉后，每3ml收集一管洗脱液。测定每一管PDE的活性，合并含有相同PDE活性的洗脱液。按上述方法分别得到含PDE1、PDE2、PDE3、PDE4、PDE5和PDE6活性酶的缓冲液进行活性测试。
步骤二：活性测试
活性测试采用氚闪烁邻近测定法进行测定，测定时所用的缓冲液含50mMTris/HClpH7.5,8.3mMMgCl2,1.7mMEGTA。
测试按下面步骤进行，在不同抑制剂浓度和少量底物存在下，加入10μl的缓冲液(50mMTris/HClpH7.5,8.3mMMgCl2,1.7mMEGTA)，适量的水使反应总体积为100μl，用固定量的酶引发反应，30℃保温30分钟，然后用50μl含有18mM硫酸锌的硅酸钇珠(1mg)终止反应，室温摇动20分钟后在MicroBetaTriLux(Perkin-ElmerLifeSciences,USA)上进行计数，然后根据计数值得出本发明化合物对酶的半数抑制率（IC50）。
所测化合物以去离子水溶解并用去离子水稀释到适当浓度，再加入缓冲液达到测试浓度。加入的活性酶组分需要控制底物水解率不超过15%，以保证水解产物与时间线性相关。为保持准确，每次测定重复三次。
抑制率计算通过下面公式进行计算：
在公式中，CPMsample表示缓冲液中同时含有待测化合物、酶和水解底物时所读出的计数值，CPMcontrol表示缓冲液中只含有酶和水解底物所读出的计数值，CPMblank表示缓冲液中只含有水解底物所读出的计数值。
IC50数值是由软件GraphPadPrism统计得到。
如图2A所示，发现咯萘啶（PYR）对PDE4有抑制活性，IC50为14.1μM，同时，如图2B所示，咯萘啶（PYR）对PDE5也表现出抑制活性，IC50为24.1μM，因此咯萘啶（PYR）是哺乳动物PDE4和PDE5的一个双重抑制剂。
而PDE蛋白的催化核心区域在各个种属之间都相当保守，因此推断咯萘啶（PYR）对恶性疟原虫PDE也有抑制活性。而疟原虫体内的PDE蛋白在它们生命周期中起着很重要的作用，对其抑制会造成致死性。
因此，咯萘啶（PYR）是哺乳动物PDE4和PDE5的双重抑制剂，也极可能是恶性疟原虫PDE的抑制剂。
实验实施例4：咯萘啶（PYR）在PDE4和PDE5中的结合模式预测
[方法和结果]
为了阐明咯萘啶（PYR）在PDE4和PDE5中的结合模式，对其进行分子对接。PDE4(PDB号:2FM0)和PDE5（PDB号：2H42）的晶体结构文件来自PDB库(http://www.rcsb.org/pdb/)。用AutoDock4.0软件将咯萘啶（PYR）对接到PDE4以及PDE5中。首先处理蛋白质，将蛋白质中的水分子、配体去除，保留金属离子，加全氢，加上Gasteiger电荷。小分子加全氢，加Gasteiger电荷。最后蛋白质和小分子都整合非极性氢。格点计算的盒子中心分别取PDE4和PDE5中带有小分子的中心。对接参数如下：ga_pop_size,150；ga_num_evals,2500000；ga_num_generations，27000；ga_run,50以及rmstol,2.0。蛋白质与分子的相互作用用拉马克遗传算法进行计算。计算过程中只考虑小分子的柔性。最后根据预测的结合自由能打分来选择结合构象进行结合模式分析。
复合物结合模式如图3A和3B所示，咯萘啶（PYR）上的甲氧基与PDE4的残基Gln369（Q369）形成氢键，图3A表明苯并喹啉结构位于由Phe372（F372）、Ile336（I336）、Met273和Tyr159（Y159）残基形成的疏水口袋中；同时，在咯萘啶（PYR）与PDE5的结合模式中，也发现它上面的甲氧基与PDE5的Gln817（Q817）形成氢键作用，苯并喹啉结构与Lue765（L765）和F820等疏水残基形成疏水相互作用。此外，如图3B所示，咯萘啶（PYR）的苯并喹啉结构上的N原子与PDE5的残基Tyr612（Y612）和Asp764（D764）形成氢键作用。而Q口袋中的氢键相互作用以及疏水作用是大多数PDE抑制剂与PDE相互作用的特征，特别是经过蛋白质序列比对，发现疟原虫PDE的蛋白质在这两个位点的氨基酸残基也是保守的，因此这一点进一步表明了咯萘啶（PYR）可与疟原虫体内的PDE相结合而抑制其活性。
因此，咯萘啶（PYR）与PDE4和PDE5的结合模式与大多数PDE的抑制剂相似，也说明咯萘啶（PYR）极大可能是疟原虫体内PDE的抑制剂。
实验实施例5：抗疟咯萘啶类化合物的选择及其抑制PDE4和PDE5活性预测
根据咯萘啶（PYR）与PDE4及PDE5的结合模式，推断当R1是具有氢键受体位点、同时具有部分疏水能力的基团；R2是具有疏水能力、并且具有氢键受体性质的基团；而R3、R4是以疏水性质为主的基团时，化合物与PDE有较高的结合能力，因此具有这些性质的咯萘啶类化合物将具有更高的抗疟原虫体内PDE活性。
表1表示优化的部分通式I所示的咯萘啶（PYR）类化合物的结合自由能（Autodock）的打分结果，这些新选择的通式I所示的咯萘啶类化合物的结合自由能低于咯萘啶（PYR）本身，表明这些化合物有更高的抑制PDE4和PDE5的活性，因此也有更高地抑制疟原虫体内PDE的活性，是活性更好的抗疟药物。
表1：部分本发明通式I所示的咯萘啶类化合物的结合自由能
实验实施例6：化合物体内抗疟活性
[方法和结果]
为了验证化合物在疟原虫体内的抗疟活性，发明人采用了Peters“4天抑制试验法”考察了化合物对红内期疟原虫的抑制作用。实验小鼠按体重灌胃给药（ｉg），为0.4ml/20g。设3个有效剂量组，每组10只小鼠，雌雄各半。4天抑制实验（4-daysuppressivetest）以原虫接种日为d0，接种后3-4h给予首剂药物，以后d1-d3每天给药1次，共计4次，d4取全部实验小鼠尾静脉制成薄血膜，甲醇固定，3%Giemsa染色20min，清水冲洗干净，晾干。以50个油镜视野（约2.5×104RBC）无性体原虫为零判为阴性。根据下式计算出各给药组的减虫率：
表2：化合物PYR90的体内抗疟活性验证
实验结果证明化合物PYR_90在的2.4mg/kg以及7.2mg/kg的剂量下减虫率都达到100%（表2），表明改造后的化合物有较强的抗疟作用。
因此，借助于反向分子对接方法并结合细胞实验确定咯萘啶（PYR）的作用靶标蛋白，进而发现咯萘啶（PYR）是一个PDE4和PDE5的双重抑制剂。过去的研究表明，咯萘啶（PYR）的抗疟靶标可能是血红素，而本发明的实验结果表明咯萘啶（PYR）的抗疟机制还应包括抑制疟原虫体内PDE活性的机理。基于这个原理，和在分子对接中获得的咯萘啶（PYR）与PDE结合作用机制的基础上，选择一系列通式I所示的PYR类化合物，并通过计算预测这些化合物对PDE的抑制活性，其是一种新作用机制的抗疟药物。并通过具体的化合物合成以及体内抗疟活性测试，验证了该系列化合物的抗疟活性。
尽管已经对本发明的具体实施方式进行了描述，但对本领域普通技术人员来说，显然在不脱离由如下权利要求所限定的本发明实质和范围的情况下，可对本发明进行各种变通和修改。
Claims (6)
1.一种如下通式I所示的咯萘啶类化合物，
其中，
R1选自以下结构中：H、Cl、
X＝F、Cl、Br或NH2；
Y＝-CH3、-CH2CH3、-CH2CH2CH3或(CH3)2CH-；
R2选自以下结构中：H、
R3选自以下结构中：
R4选自以下结构：
其中，通式I所示的咯萘啶类化合物不包括R1为Cl，R2为H，R3为且R4为的化合物。
2.如权利要求1所述的通式I所示的咯萘啶类化合物具体为：
3.如权利要求1或2所述的咯萘啶类化合物在制备抗疟的药物中的用途。
4.如权利要求1或2所述的咯萘啶类化合物在制备疟原虫体内PDE抑制剂的药物中的用途。
5.如权利要求4所述的用途，其中，所述疟原虫体内PDE是PfPDE。
6.一种药物组合物，其特征在于，所示药物组合物包含权利要求1或2所述的咯萘啶类化合物作为主要成分以及药学上可接受的各种辅剂。
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