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2002 Fiscal Year Final Research Report Summary

Development of new antimalarial endoperoxides and it's antimalarial mechanism

Research Project

Project/Area Number 13672286
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionOKAYAMA UNIVERSITY

Principal Investigator

KIM Hye-sook  Okayama University ・ the Graduate School of Natural Science and Technology, Associate Professor, 大学院・自然科学研究科, 助教授 (70314664)

Co-Investigator(Kenkyū-buntansha) WATAYA Yusuke  Okayama University ・ the Graduate School of Natural Sciences and Technology, Professor, 大学院・自然科学研究科, 教授 (90127598)
Project Period (FY) 2001 – 2002
KeywordsMalaria / Drug-resistant / Endoperoxides / New antimalarials / hemoglobin degradation / protease inhibitor
Research Abstract

Malaria control become more complexes because causal agent Plasmodium falciparum has developed resistance to nearly all available antimalarial drugs. As malaria parasite are increasingly resistance to more common and effective alkaloid drugs, interest in the antimalarial properties of nonalkaloid compounds such as sesquiterpene artemisinin and the related endoperoxides is rapidly growing. The search for novel antimalarial drugs against specific parasite target is thus an urgent task to pursue.
Malaria parasites invade human erythrocytes in the erythrocytic stage of infection. While residing in erythrocytes, the parasites depend on hemoglobin as a source of food, digesting it with a series of proteases. Two homologous aspartic proteases called plasmepsin I and II initiate the degradative process by cleaving the native hemoglobin molecule in a highly conserved hinge region. A cysteine protease falcipain-2, and a metalloprotease falcilysin, act further downstream in the pathway to degrade … More hemoglobin to small peptides. Inhibition of these proteases kill parasites in culture and animal model, suggesting that hemoglobin degrading proteases are valid targets for chemotherapy.
In this study, we studied development and selection of new antimalarial endopeoxides using about 300 analogs of synthetic endoperoxides. As a results, antimalarial activity of a synthetic endoperoxide, (N-89) was selected using in vitro against Plasmodium falciparum and in vivo against P. bergheii. In vitro N-89 exhibited potent antimalarial activity against chloroquine-sensitive (FCR-3) and chloroquine-resistant (K1) strain, estimated 50% growth inhibitory concentration (IC_<30>) was 28 nM and 26 nM, respectively. In vivo antimalarial activity of the compound was also remarkable, ED_<50> and ED_<90> were 20 mgkg^<-1> and 40 mgkg^<-1>, respectively. Differential effect was found at different developmental stages in vitro. N-89 is more sensitive on early and middle stages parasites and less sensitive on late and schizont stage parasites. The effect was associated with distinct morphological changes. Although late and schizonts stage parasites entered 2^<nd> cycle, their re-invasion was impaired. Consistence with stage-specific effect, inhibition of hemozoin formation is pronounced at mature stage parasites than schizonts. When middle trophozoites stage parasites was incubated with endoperoxide hemoglobin accumulation was found in parasite lysates. An aspartic protease inhibitor of malaria parasite pepstatin A could reverse its hemoglobin accumulation activity, and pepstatin A showed antagonistic effect when combined with N-89. Our results explain antimalarial activity of N-89 may be related to hemoglobin degradation. Less

  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 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)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kim, H.-S., Begum, K., Ogura, N., Wataya, Y., Tokuyasu, T., Masuyama, A., Nojima, M., McCullough, K.J.: "The antimalarial activity of yingzhaosu A analogues"J.Med.Chem.. 45(21). 4732-4736 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takasu, K., Inoue, H., Kim, H.-S., Suzuki, M., Shishido, M., Wataya, Y., Ihara, M.: "Rhodacyanine dyes as antimalarials. 1. Antimalarial activity and toxicity of rhodacyanine dyes"J.Med.Chem. 45(5). 995-998 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hamada, Y., Tokuhara, H.Masuyama, A., Nojima, M., Kim, H.-S., Ono, K., Ogura, N., Wataya, Y.: "Synthesis and Notable Antimalarial Activity of Acyclic Peroxides, I-(Alkyldioxy)-1-(methyldioxy) cyclododecanes"J.Med.Chem.. 45(6). 1374-1378 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shuto, S., Niizuma, S., Minakawa, N., Kim, H.-S., Wataya, Y., Matsuda, A.: "New neplanocin analogs 12. An alternative synthesis of (6,R)-6'-C-methylneplanocin A(RMNPA), a novel potent anti-malarial agent"J.Med.Chem.. 45(3). 748-751 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kikuchi, H., Tasaka, H., Hirai, S., Takaya, Y., Iwabuchi, Y., Ooi, H., Hatakeyama, S., Kim, H.-S., Wataya, Y., Oshima, Y.: "Potent antimalarial febrifugine analogues against, the Plasmodium malaria parasite"J.Med.Chem.. 45(12). 2563-2570 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kamata, M., Ohra, M., Komatsu, K., Kim, H.-S., Wataya, Y.: "Synthesis, Fe(II)-induced degradation, and antimalarial activities of 1,5-diaryl-6,7-dioxabicyclo [3.2.2]nonanes : direct evidence for nucleophilic O-1,2-aryl shifts"Tetrahedron letters. 43. 2063-2067 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kamata, M., Kudoh, T., Kaneko, J., Kim, H.-S., Wataya, Y.: "Fe(II)-mediated fragmentation of I,4-diaryl-2,3-dioxabicyclo-[2.2.2]octanes through competitive single electron transfer pathway and Lewis acid pathway"Tetrahedron letters. 43. 617-620 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi, Y., Koike, M., Azuma, K., Nishioka, H., Abe, H., Kim, H-S., Wataya, Y., Harayama, T.: "Synthesis and antimalarial activity of febrifugine derivatives"Chem., Pharm.Bull.. 49. 721-725 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takasu, K., Katagiri, R., Tanaka, Y., Toyoda, M., Kim, H.-S., Wataya, Y., Ihara, M.: "Synthesis of a novel artemisinin analog having potent antimalarial activity"Heterocycles. 54. 607-610 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi, Y., Azuma, K., Takakura, K., Abe, H., Kim, H.-S., Wataya, Y., Harayama, T.: "Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction"Tetrahedron. 57. 1213-1218 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kim, H.-S., Nagai, Y., Ono, K., Begum, K., Wataya, Y., Hamada, Y., Tsuchiya, K., Masuyama, A., Nojima, M., McCullough, K.J.: "Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes"J.Med.Chem.. 44. 2357-2361 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tokuyasu, T., Masuyama, A., Nojima, M., McCullough, K.J., Kim, H.-S., Wataya, Y.: "Yingzhaosu A Analogues : Synthesis by the ozonolyis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity"Tetrahedron. 57. 5979-5989 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mi-ichi, F., Takeo, S., Takashima, E., Kobayashi, T., Kim, H.-S., Wataya, Y., Matsuda, A., Toni, M., Tsuboi, T., Kita, K.: "Unique properties of respiratory chain in Plasmodium falciparum mitochondria.Tropical ddisease : Molecular to bedside"Kluwen Academic/Plenum publications(in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 綿矢有佑, 金 惠淑: "「誰にでもわかる遺伝子検査」(13)感染症-マラリア"検査と技術. 3 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 綿矢有佑, 金 惠淑: "マラリアのゲノム診断"現代医療. 6 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takasu, K., Terauchi, H., Inoue, H., Kim, H.-S., Wataya, Y. and Ihara, M.: "Parallel synthesis of antimalarial rhodacyanine dyes by the combination of three components in one-pot"Journal of Combinatorial Chemistry. (In Press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Begum, K., Kim, H.-S., Kumar, V., Stojiljkovic, I. And Wataya, Y.: "In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum"Parssitol.Res.. (In press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kamata, M., Satoh, C., Kim, H.-S. and Wataya, Y.: "Iron (II) promoted rearrangement of 1, 4-diaryl-2, 3-dioxabicyclo[2.2.2]oct-5-enes : a mechanism distinct from that postulated previously"Tetrahedron Letters. 43(46). 8313-8317 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kim, H.-S., Begum, K., Ogura, N., Wataya, Y., Nonami, Y., Ito, T., Masuyama, A., Nojima, M. and McCullough, K. J.: "Antimalarial activity of 1, 2, 5, 6-tetraoxacycloalkanes and 1, 2, 5-trioxacycloalkanes"J.Med.Chem.. (In Press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Murakami, N., Sugimoto, M., Kawanishi, M., Tamura, S., Kim, H.-S., Begum, K., Wataya, Y. and Kobayashi, M.: "New semi-synthetic quassinoids with in vivo antimalarial activity"J.Med.Chem.. 46(4). 638-641 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kim, H.-S., Begum, K., Ogura, N., Wataya, Y., Tokuyasu, T., Masuyama, A., Nojima, M. and McCullough, K. J.: "The antimalarial activity of yingzhaosu A analogues"J.Med.Chem.. 45(21). 4732-4736 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takasu, K., Inoue, H., Kim, H.-S., Suzuki, M., Shishido, M., Wataya, Y. and Ihara, M.: "Rhodacyanine dyes as antimalarials. 1. Antimalarial activity and toxicity of rhodacyanine dyes"J.Med.Chem.. 45(5). 995-998 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hamada, Y., Tokuhara, H., Masuyama, A., Nojima, M., Kim, H.-S., Ono, K., Ogura, N. and Wataya, Y.: "Synthesis and Notable Antimalarial Activity of Acyclic Peroxides, 1-(Alkyldioxy)-1-(methyldioxy)cyclododecanes"J.Med.Chem.. 45(6). 1374-1378 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shuto, S., Niizuma, S., Minakawa, N., Kim, H.-S., Wataya, Y. and Matsuda, A.: "New neplanocin analogs 12. An alternative synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA), a novel potent anti-malarial agent"J.Med.Chem.. 45(3). 748-751 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kikuchi, H., Tasaka, H., Hirai, S., Takaya, Y., Iwabuchi, Y., Ooi, H., Hatakeyama, S., Kim, H.-S., Wataya, Y. and Oshima, Y.: "Potent antimalarial febrifugine analogues against the Plasmodium malaria parasite"J.Med.Chem.. 45(12). 2563-2570 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kamata, M., Ohta, M., Komatsu, K., Kim, H.-S. and Wataya, Y.: "Synthesis, Fe(II)- induced degradation, and antimalarial activities of 1, 5-diaryl-6, 7-dioxabicyclo [3.2.2]nonanes : direct evidence for nucleophilic O-1, 2-aryl shifts"Tetrahedron letters. 43. 2063-2067 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kamata, M., Kudoh,T., Kaneko, J., Kim, H.-S. and Wataya, Y.: "Fe(II)-mediated fragmentation of 1, 4-diaryl-2, 3-dioxabicyclo-[2.2.2]octanes through competitive single electron transfer pathway and Lewis acid pathway"Tetrahedron letters. 43. 617-620 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Iwasa, K., Moriyasu, M., Tachibana, Y., Kim, H.-S., Wataya, Y., Wiegrebe, W., Bastow, K. F., Cosentino, L. M., Kozuka, M. and Lee, K.-H.: "Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HTV agents"Bioorg.Med.Chem.. 9. 2871-2884 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hayashi, M., Taniguchi, S. Ishizuka, Y., Kim, H.-S., Wataya, Y., Yamamoto, S. And Moriyama, Y.: "A Homologue of N-ethylmaleimide-sensitive factor in the malaria parasite, Plasmodium falciparum, is exported and localized in vesicular structures in the cytoplasm of infected erythrocyte in the brefeldin A-sensitive pathway"J.Biol.Chem.. 276. 15249-15255 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kim, H.-S., Nagai, Y., Ono, K., Begum, K., wataya, Y., Hamada, Y., Tsuchiya, K., Masuyama, A., Nojima, M. and McCullough, K.J.: "Synthesis and antimalarial activity of novel medium-sized 1, 2, 4, 5-tetraoxacycloalkanes"J.Med.Chem.. 44(14). 2357-2361 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tokuyasu, T., Masuyama, A., Nojima. M., McCullough, K. J., Kim, H.-S. and Wataya, Y. Yingzhaosu A.: "Analogues : Synthesis by the ozonolyis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity"Tetrahedron. 57. 5979-5989 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujishima, H., Takeshita, H., Toyota, M., Kim, H.-S., Wataya, Y., Tanaka, M., Sasaki, T. And Ihara, M.: "Antimalarial and cytotoxic activities of bicyclo[6.4.0]dodecanes"Chem., Pharm., Bull.. 49(5). 572-575 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi, Y., Azuma, K., Takakura, K., Abe, H., Kim, H.-S., Wataya, Y. and Harayama, T.: "Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction"Tetrahedron. 57. 1213-1218 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takasu, K., Katagiri, R., Tanaka. Y., Toyoda, M., Kim, H.-S., Wataya, Y. and Ihara, M.: "Synthesis of a novel artemisinin analog having potent antimalarial activity"Heterocycles. 54(2). 607-610 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi, Y., Koike, M., Azuma, K., Nishioka, H., Abe, H., Kim, H-S., Wataya, Y., and Harayama, T.: "Synthesis and antimalarial activity of febrifugine derivatives"Chem., Pharm.Bull.. 49(6). 721-725 (2001)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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