Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

• 資料種別: 博士論文
• ISSN: 1422-0067
• タイトル: Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase
• 巻次・部編番号: 22 13
• 著者・編者: Hartuti, Endah Dwi
• 著者標目: Hartuti, Endah Dwi
• 出版事項: MDPI
• 出版年月日等: 2021-09-17
• 出版年（W3CDTF）: 2021-09-17
• 並列タイトル等: 熱帯熱マラリア原虫ジヒドロオロト酸脱水素酵素の新規選択的阻害剤の同定
• タイトル（掲載誌）: International Journal of Molecular Sciences
• 授与機関名: Nagasaki University (長崎大学)
• 授与年月日: 2021-09-17
• 授与年月日（W3CDTF）: 2021-09-17
• 報告番号: 甲医歯薬第1370号
• 学位: 博士(医学)
• 博論授与番号: 甲医歯薬第1370号
• 本文の言語コード: eng
• 件名標目: Plasmodium falciparum; dihydroorotate dehydrogenase; inhibitor screening; ubiquinone; antimalarial drug
• 対象利用者: 一般
• 一般注記: Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.; 長崎大学学位論文 学位記番号:博(医歯薬)甲第1370号 学位授与年月日:令和3年9月17日; Author: Endah Dwi Hartuti, Takaya Sakura, Mohammed S. O. Tagod, Eri Yoshida, Xinying Wang, Kota Mochizuki, Rajib Acharjee, Yuichi Matsuo, Fuyuki Tokumasu, Mihoko Mori, Danang Waluyo, Kazuro Shiomi, Tomoyoshi Nozaki, Shinjiro Hamano, Tomoo Shiba, Kiyoshi Kita and Daniel Ken Inaoka; Citation: International Journal of Molecular Sciences, 22(13), art. no. 7236; 2021; identifier:Nagasaki University (長崎大学), 博士(医学) (2021-09-17); http://hdl.handle.net/10069/00040957
• DOI: info:doi/10.3390/ijms22137236; https://doi.org/info:doi/10.3390/ijms22137236
• 国立国会図書館永続的識別子: info:ndljp/pid/12154365; https://dl.ndl.go.jp/pid/12154365
• コレクション（共通）: 障害者向け資料
• コレクション（障害者向け資料：レベル1）: テキストデータ
• コレクション（個別）: 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• 収集根拠: 博士論文（自動収集）
• 受理日（W3CDTF）: 2022-03-06T04:54:00+09:00
• 作成日（W3CDTF）: 2022-02-10
• 記録形式（IMT）: PDF
• オンライン閲覧公開範囲: 国立国会図書館内限定公開
• デジタル化資料送信: 図書館・個人送信対象外
• 遠隔複写可否（NDL）: 可
• 関連情報（URI）: http://hdl.handle.net/10069/00040957
• 掲載誌（URI）: http://hdl.handle.net/10069/00041253
• 連携機関・データベース: 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp