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

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 14021072
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: OKAYAMA UNIVERSITY
• Principal Investigator: WATAYA Yusuke Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (90127598)
• Project Period (FY): 2002 – 2005
• Keywords: malaria / endoperoxides / drug-resistant / antimalarials / johzan alkaloid / mechanism analysis

Research Abstract

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.

Research Products

• [Journal Article] Antimalarial Effect of Bis-pyridinium Salts, N, N'-Nexamethylenebis (4-carbamoyl-1-alkylpyridinium bromide). (2006)
  • Author(s): Fujimoto, K., Morisaki, D., Yoshida, M., Namba, T., Kim, H.-S., Wataya, Y., Kourai, H., Kakuta, H., Sasaki, K.
  • Journal Title: Bioorg. Med. Chem. Lett. (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antimalarial Effect of Bis-pyridinium Salts, N,N'-Hexamethylenebis (4-carbamoy1-1- alkylpyridinium bromide). (2006)
  • Author(s): Fujimoto, K., Morisaki, D., Yoshida, M., Namba, T., Kim, H.-S., Wataya, Y., Kourai, H., Kakuta, H., Sasaki, K.
  • Journal Title: Bioorg. Med. Chem. Lett. 16 Pages: 2758-2760
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and evaluation of □-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis. (2005)
  • Author(s): Takasu, K, Shimogama, T, Saiin, C, Kim, H.-S, Wataya, Y, Brun, R, Ihara, M.
  • Journal Title: Chem. Pharm. Bull. 53.6 Pages: 653-661
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Co-catalyzed autoxidation of alkene in the presence of silane. The effect of the structure of silanes on the efficiency of the reaction and on the product distribution. (2005)
  • Author(s): Wu, J.-M., Kunikawa, S., Tokuyasu, T., Masuyama, A., Nojima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Tetrahedron 61 Pages: 9961-9968
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and biological activity of fatty acid conjugate of quinine. (2005)
  • Author(s): Kumura, N., Izumi, M., Nakajima, S., Shimizu, S., Kim, H.-S., Wataya, Y, Baba, N.
  • Journal Title: Biosci. Biotech. Biochem. 69.11 Pages: 2250-2253
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of novel siRNAs having thymidine dimers consisting of a carbamate or an urea linkage at their 3' overhang regions and their ability to suppress human RNase L protein expression. (2005)
  • Author(s): Ueno, Y., Naito, T., Kawada, K., Shibata, A., Kim, H.-S., Wataya, Y, Kitade, Y.
  • Journal Title: Biol. Biophy. Res. Comm. 20, 330.4 Pages: 1168-1175
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to the parasite S-adenosyl homocysteine hydrolase Inhibition. (2005)
  • Author(s): Takagi, T., Sukeda, M., Kim, H.-S., Wataya, Y, Kitade, Y., Matsuda, A., Shuto.S.
  • Journal Title: Org. Biomol. Chem. 3 Pages: 1245-1251
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 1,2,4,5-Tetraoxan cycloalkanes : Synthesis and Antimalarial Activity. (2005)
  • Author(s): Masuyama, A., Wu, J-M., Nojima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Mini-Reviews Med. chem. 5 Pages: 1035-1043
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sequence analysis of the 5'flanking regions of human dihydropyrimidine dehydrogenase gene : Identification of a new polymorphism related with effects of 5-fluorouracil. (2005)
  • Author(s): Hasegawa, T., Kim, H.-S., Fukushima, M., Wataya, Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24.4 Pages: 233-242
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory Mechanisms of 1-(3-Cethynyl-□-D-ribo-pentofuranosyl)uracil(EUrd)on RNAsynthesis. (2005)
  • Author(s): Yokogawa, T, Kanda, H., Takatori, S, Takenaka, K, Naito, T., Sasaki, T, Matsuda, A., Fukushima, M., Kim, H.-S, Wataya, Y.I
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24.3 Pages: 227-232
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis and evaluation of □-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis. (2005)
  • Author(s): Takasu, K, Shimogama, T, Saiin, C, Kim, H.-S, Wataya, Y, Brun, R, Ihara, M.
  • Journal Title: Chem. Pharm. Bull. 53 (6) Pages: 653-61
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and biological activity of fatty acid conjugate of quinine. (2005)
  • Author(s): Kumura, N., Izumi, M., Nakajima, S., Shimizu, S., Kim, H.-S., Wataya, Y., Baba, N.
  • Journal Title: Biosci. Biotech. Biochem. 69(11) Pages: 2250-2253
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of novel siRNAs having thymidine dimers consisting of a carbamate or an urea linkage at their 3' overhang regions and their ability to suppress human RNase L protein expression. (2005)
  • Author(s): Ueno, Y., Naito, T., Kawada, K., Shibata, A., Kim, H.-S., Wataya, Y., Kitade, Y.
  • Journal Title: Biol. Biophy. Res. Comm. 20, 330(4) Pages: 1168-1175
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to the parasite S-adenosyl homocysteine hydrolase Inhibition. (2005)
  • Author(s): Takagi, T., Sukeda, M., Kim, H.-S., Wataya, Y., Kitade, Y., Matsuda, A., Shuto.S.
  • Journal Title: Org. Biomol. Chem. 3 Pages: 1245-1251
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 1,2,4,5-Tetraoxan cycloalkanes : Synthesis and Antimalarial Activity. (2005)
  • Author(s): Masuyama, A., Wu, J-M., Nojima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Mini-Reviews Med. Chem. 5 Pages: 1035-1043
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sequence analysis of the 5--flanking regions of human dihydropyrimidine dehydrogenase gene : Identification of a new polymorphism related with effects of 5-fluorouracil. (2005)
  • Author(s): Hasegawa, T., Kim, H.-S., Fukushima, M., Wataya,Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24 (4) Pages: 233-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory Mechanisms of 1-(3-C-ethynyl-^-D-ribo-pentofuranosyl)uracil (EUrd) on RNA Synthesis. (2005)
  • Author(s): Yokogawa, T., Kanda, H., Takatori, S., Takenaka, K., Naito, T., Sasaki, T., Matsuda, A., Fukushima, M., Kim, H.-S., Wataya, Y.
  • Journal Title: Nucleosides Nucleotides Nucleic Acids 24 (3) Pages: 227-232
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 実験医学 (2005)
  • Author(s): 綿矢有佑, 金恵淑
  • Total Pages: 5
  • Publisher: 抗マラリア薬の開発 : 過去-現在-未来
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] ヘムへの配位能を有する抗マラリア活性化合物 (2006)
  • Inventor(s): 樋口恒彦, 大宮弘久, 梅澤直樹, 金恵淑, 綿矢有佑
  • Industrial Property Rights Holder: 樋口恒彦
  • Industrial Property Number: 特願2006-49678
  • Filing Date: 2006-02-28
  • Description: 「研究成果報告書概要(和文)」より