CN105796539A - 豨莶酸在制备治疗疟疾药物中的应用 - Google Patents
豨莶酸在制备治疗疟疾药物中的应用 Download PDFInfo
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Abstract
本发明提供了豨莶酸在制备治疗疟疾药物中的应用，豨莶酸的结构式如下：
Description
技术领域
本发明涉及药物，具体涉及化合物豨莶酸在制备治疗疟疾药物中的应用，尤其涉及化合物豨莶酸在制备治疗由疟原虫引起的疟疾药物中的应用。
背景技术
疟疾是地球上发生最频繁的寄生虫病，是由按蚊进行传播、具有潜在致命危险的疾病。每年全球有5亿左右的疟疾病例，导致超过100万人死亡，绝大部分发生在非洲。世界卫生组织指出疟疾平均每30秒杀死一个5岁以下的儿童。疟疾由疟原虫引起。带有疟原虫的雌按蚊叮咬人体后，将疟原虫注入人体，经10～20天会发生典型的疟疾临床症状，可分为四期：发冷期、发热期、出汗期和间歇期。疟疾的反复发作后，病人会出现贫血、肝脾肿大，甚至出现脑型、超高热型、厥冷型和胃肠型等凶险症状，甚至危及生命。随着已有抗疟药物的耐药性的不断增加，疟疾的发病率日益增加，亟待具有新型治疗作用的抗疟药物的发现。
中医中药治疗疟疾已经有很长的历史，比如在《素问·刺疟论》中就提出了用针灸预防治疗疟疾，在中草药方面，除了闻名世界的青蒿外，威灵仙、水蜈蚣、鸦胆子、常山、鹅不食草、槟榔、翻白草、石龙芮等也在民间用来治疗疟疾。从中药青蒿中发现的活性化合物青蒿素用于治疗疟疾取得了很好的效果，广泛用于临床，因此从中药中寻找具有抗疟活性的化合物意义重大。本发明人通过多年研究发现豨莶草中的化学成分豨莶酸(siegesbeckic acid)具有显著抗疟作用。
豨莶草为菊科植物豨莶Siegesbecki aorientalis L.、腺梗豨莶Siegesbeckiapubescens Makino或毛梗豨莶Siegesbeckia glabrescens Makino的干燥地上部分。中医理论认为豨莶草性寒，味辛、苦，用于风湿痹痛、筋骨无力等。尚未见豨莶草中的化学成分具有抗疟作用的报道。
发明内容
本发明所要解决的技术问题在于提研究设计豨莶酸在制备治疗疟疾药物中的应用。
本发明提供了豨莶酸在制备治疗疟疾药物中的应用。
豨莶酸的结构式如下：
豨莶酸系从豨莶、腺梗豨莶或毛梗豨莶中分离得到的化合物。
体外抗疟活性测定结果显示，豨莶酸有较好的体外抗疟原虫活性。因此，可用于制备治疗疟疾的药物。
本发明的另一目的是提供以豨莶酸为活性成分，用于制备治疗疟疾的药物组合物，尤其用于制备治疗由疟原虫引起的疟疾的药物组合物。
本发明所述药物组合物含有治疗有效量的豨莶酸为活性成分，以及含有一种或多种药学上可接受的载体。其中活性成分在药物组合物中的重量为5-95％。
所述药学上可接受的载体是指药学领域常规的药物载体，例如：豨释剂、赋形剂如水灯；填充剂如淀粉、蔗糖等；粘合剂如明胶、聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如碳酸钙、碳酸氢钠；吸收促进剂如季铵化合物；表面活性剂如十六烷醇；吸附载体如高岭土和皂粘土；润滑剂如滑石粉、硬脂酸钙、聚乙二醇等、另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明化合物可以组合物的形式通过口服、鼻吸入、直肠或肠胃外给药的方式施用于需要这种治疗的患者。用于口服时，可将其职称常规的固体制剂如片剂、颗粒剂、胶囊等或制成液体制剂如水或油悬浮剂、糖浆等；用于肠胃外给药时，可将其制成注射用的溶液、水货油性悬浮剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合，然后将其制成所需的剂型。
具体实施方式
实施例1：豨莶酸的制备
豨莶的干燥地上部分10kg粉碎后，以10倍量90％乙醇回流3次，每次2小时，合并提取液，减压回收溶剂，得乙醇提取物，该提取物上大孔树脂HP-20柱，分别用蒸馏水和30％EtOH洗脱至洗脱液无色，回收80％EtOH洗脱液至干，得80％EtOH洗脱部分。将80％EtOH洗脱部分进行硅胶柱层析，以氯仿-甲醇5∶1进行梯度洗脱，用薄层层析检查层析流分，具有相同单一斑点的流分合并，浓缩，分得流分1、2、3、4、5，将其中的第3和第4部分再分别进行正相硅胶柱层析，以不同比例的氯仿-甲醇进行洗脱，再经反复RP-C18层析(MeOH∶H2O)分离、纯化，得到豨莶酸146mg。制得的豨莶酸用于实施例2。
豨莶酸(Siegesbeckic acid)，白色结晶，分子式：C20H32O4。经光谱数据分析和理化性状测定与文献报道Guo DA，Zhang ZG，Ye GQ，Lou ZC.Studies onliposoluble constituents from the aerial parts of Siegesbeckia orientalis L.Yao XueXue Bao.1997Apr；32(4)：282-5.)的豨莶酸完全一致。
实施例2：豨莶酸体外抗疟活性测定
抗疟活性可以通过测量疟原虫LDH活性来确定(Jain，M.；Khan，S.I.；Tekwani，B.L.；Jacob，M.R.；Singh，S.；Singh，P.P.；Jain，R.Synthesis，antimalarial，antileishmanial.and antimicrobial activities of some 8-quinolinamine analogues.Bioorg.Med.Chem.2005，13，4458-4466.)。在含10μL连续豨释测试样本的96孔板的每个孔中加入感染了D6 or W2株P.falciparum的红细胞混悬液(200μL，在RPMI 1640培养集中加入10％人血清和60lg/mL阿米卡星，使疟原虫血症达到2％，红细胞压积达到2％)，然后用90％N2，5％O2，and 5％CO2组成的混合气体冲洗板，在培育房内培育72小时，温度保持在37℃。LDH活性用MalstatTM试剂(Flow Inc.，Portland，OR)测定，测定程序参照Makler和Hinrichs的程序(M.T.Makler and D.J.Hinrichs，Measurement of the lactate dehydrogenase activity ofPlasmodium falciparum as an assessment of parasitemia.J.Am.J.Trop.Med Hyg.1993，48(2)：205-210)。简要说来，就是将20μL培育的混合物同100μL he MalstatTM试剂混合，在室温下培育30分钟.然后加入20微升NBT/PES的混合物(NBT/PES比例为1∶1)(Sigma，St.Louis，MO)，在黑暗条件下培育1小时。之后，加入100μL5％醋酸溶液终止这一反应，并用650nm来检测板.药物对照组中加入青蒿素和氯喹。从剂量-效应曲线中计算出IC50。测定化合物抗疟活性的选择性指标时，也要测定他们在体外对哺乳动物细胞的毒性.测试在96孔组织培养板中进行(J.Mustafa，S.I.Khan，G.Ma，L.A.Walker and I.A.Khan，Synthesis and AnticancerActivities of Fatty Acid Analogs of Podophyllotoxin.Lipids.2004，39(2)：167-172.)。在96孔板中以25,000个/孔的密度种植非洲绿猴肾异倍体细胞并培育24小时.加入不同浓度的样品，即豨莶酸化合物溶液，浓度为528.8ng/ml、1586.4ng/ml、4760g/ml，继续培育48小时。利用Neutral Red assay方法测定存活细胞数，从剂量-效应曲线中计算出IC50。用阿霉素作为阳性对照药物。豨莶酸的对D6和W2的IC50值如下表：
结果显示，豨莶酸有较好的体外抗疟原虫活性。
Claims (4)
1.豨莶酸在制备治疗疟疾药物中的应用，其特征在于豨莶酸的结构式如下：
2.根据权利要求1所述的应用，其特征在于所述药物为治疗由疟原虫引起的疟疾的药物。
3.一种治疗疟疾的药物组合物，其特征在于含有如权利要求1中所述的豨莶酸和药学上可以接受的载体。
4.根据权利要求3所述的药物组合物，其特征在于活性成分豨莶酸在药物组合物中的重量含量为5-95％。
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| MINA LEE,ET AL: "ent-Kaurane and ent-Pimarane Diterpenes from Siegesbeckia pubescens Inhibit Lipopolysaccharide-Induced Nitric Oxide Production in BV2 Microglia", 《BIOL. PHARM. BULL》 * |
| RUI WANG ET AL: "In vitro anti-inflammatory effects of diterpenoids and sesquiterpenoids from traditional Chinese medicine Siegesbeckia pubescens", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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