New antiamlarial drug development research including mechanism analysis of drug-resistant Plasmodium falciparum

抗疟新药开发研究，包括恶性疟原虫耐药机制分析

• 批准号: 14021072
• 负责人: WATAYA Yusuke
• 金额: $ 35.2万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14021072/
• 关键词: malaria; endoperoxides; drug-resistant; antimalarials; johzan alkaloid; mechanism analysis; 薬剤耐性; Heat Shock Protein; 環状過酸化化合物; ゲルダナマイシン; 環状下酸化物; pfmdr 1; アルテミシニン耐性; heat shock protein

Current situation of the malaria becomes serious more and more and recently, drug-resistant Plasmodium falciparum malaria parasites, human infected severe malaria, has increased drug-resistant P. falciparum malaria.Our research objective is development of new antiamalarial drug against drug-resistant P. falciparum and our study is advanced for the purpose of contributing to the malaria control. For the dissolve the antimalarial action, we used new antimalarial organic compounds, endoperoxides, with molecular biology and computor based drug-target techniques. Our final goal of research is control of malaria from the on earth.The research result of this study is shown at the following.We synthesized the 150 g of 1,2,4,5-tetraoxacycloalkane (N-89) including improvement of synthtic steps for supply of cheap price in the malaria endemic areas and research of suitable solvent for good manufactured practice during synthetic steps.It's antimalarial test for monkey malaria parasite infected monkey was done. As a result, N-89 has high antimalarial activities for monkey malaria with no any cytotoxic effect. Finally, malarial parasites infected monkey cured for N-89 treatment of oral route. Also our compound has no side effect treatment with 2,000 mg/kg of N-89, weight loss, biological composition of blood, behavior, against rat.Pharmacokinetic study of N-89, blood concentration level of N-89 was 1×10^<-7> M, and this concentration was also kept 5 hours after N-89 treatment. Blood level of N-89 concentration was sufficient for kill the malaria parasite in the blood. During pharmacokinetic parameter analysis, our compound have short half time in the blood stream (t_<1/2>=45 min) and shows the high bioavailability (BA=58.6%). In conclusion, Our compoud can be expected as a new antimalarial drug.

近年来，恶性疟原虫耐药、人感染重症疟疾的发生，使耐药恶性疟原虫疟疾的发病率不断上升，本课题的研究目标是开发针对耐药恶性疟原虫的新的抗疟药物，为疟疾的防治做出贡献。为了溶解抗疟作用，我们使用了新的抗疟有机化合物，内过氧化物，分子生物学和基于计算机的药物靶向技术。本研究的最终目的是从地球上控制疟疾，本研究的研究结果如下：我们合成了150 g的1，2，4，5-四氧杂环烷烃（N-89）包括改进合成步骤，为疟疾流行区提供廉价的原料，研究合成步骤中适宜的溶剂，为生产提供良好的操作规范，并进行猴疟原虫抗疟试验被感染的猴子。因此，N-89对猴疟疾具有高抗疟活性，且无任何细胞毒性作用。最后，疟疾寄生虫感染的猴子通过口服N-89治疗而治愈。此外，我们的化合物用2，000 mg/kg的N-89治疗，体重减轻，血液生物组成，行为，对大鼠没有副作用。N-89的药代动力学研究，N-89的血液浓度水平为1×10 - 4 μ <-7>M，并且该浓度在N-89治疗后也保持5小时。血中N-89浓度足以杀死血液中的疟原虫。在药动学参数分析中，该化合物在血液中半衰期短（t1/2&gt;=45 min），生物利用度高（BA=58.6%）。因此，本化合物有望成为一种新的抗疟药物。

项目成果

Synthesis and biological activity of fatty acid conjugate of quinine.

奎宁脂肪酸结合物的合成及其生物活性。

• 发表时间: 2005
• 期刊: Biosci.Biotech.Biochem., 69(11)
• 作者: Kumura;N.;Izumi;M.;Nakajima;S.;Shimizu;S.;Kim;H.-S.;Wataya;Y.;Baba;N.
• 通讯作者: N.

Inhibitory Mechanisms of 1-(3-C-ethynyl-b-D-ribo-pentofuranosyl) uracil ( EUrd ) on RNA Synthesis.

1-(3-C-乙炔基-b-D-核糖-呋喃戊糖基)尿嘧啶 (EUrd) 对 RNA 合成的抑制机制。

• 发表时间: 2005
• 期刊: Nucleosides Nucleotides Nucleic Acids, 24(3)
• 作者: Yokogawa;T.;Kanda;H.;Takatori;S.;Takenaka;K.;Naito;T.;Sasaki;T.;Matsuda;A.;Fukushima;M.;Kim;H-S.;Wataya,Y.
• 通讯作者: Wataya,Y.

Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to the parasite S-adenosyl homocysteine hydrolase Inhibition

合成 5-亚甲基马里斯霉素及其 2-氟同源物，通过抑制寄生虫 S-腺苷同型半胱氨酸水解酶而具有有效的抗疟活性

• 发表时间: 2005
• 期刊: Org.Biomol.Chem., 3
• 作者: Takagi;T.;Sukeda;M.;Kim;H.-S.;Wataya;Y.;Kitade;Y;Matsuda;A.;Shuto.S.
• 通讯作者: Shuto.S.

Kim, H.-S., Begum, K., Ogura, N., Wataya, Y., Nonami, Y., Ito, T., Masuyama, A., Nojima, M., McCullough, K.J.: "Antimalarial activity of 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes"J. Med. Chem.. (in press). (2003)

Kim, H.-S.、Begum, K.、Ogura, N.、Wataya, Y.、Nonami, Y.、Ito, T.、Masuyama, A.、Nojima, M.、McCullough, K.J.：“抗疟活性

Murakami, N., Sugimoto, M., Kawanishi, M., Tamura, S., Kim, H.-S., Begum, K., Wataya, Y., Kobayashi, M.: "New semi-synthetic quassinoids with in vivo antimalarial activity"J. Med. Chem.. 46(4). 638-641 (2003)

Murakami, N.、Sugimoto, M.、Kawanishi, M.、Tamura, S.、Kim, H.-S.、Begum, K.、Wataya, Y.、Kobayashi, M.：“新型半合成苦木素