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

• Material Type: 博士論文
• Title: 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
• Author/Editor: Hartuti, Endah Dwi
• Author Heading: Hartuti, Endah Dwi
• Publication, Distribution, etc.: MDPI
• Publication Date: 2021-09-17
• Publication Date (W3CDTF): 2021-09-17
• Alternative Title: 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
• Periodical title: International Journal of Molecular Sciences
• No. or year of volume/issue: 22 13
• Volume: 22
• Issue: 13
• Pages: 7236-
• ISSN (Periodical Title): ISSN : 1422-0067
• Degree grantor/type: Nagasaki University (長崎大学)
• Date Granted: 2021-09-17
• Dissertation Number: 甲医歯薬第1370号
• Degree Type: 博士(医学)
• Text Language Code: eng
• Subject Heading: Plasmodium falciparum; dihydroorotate dehydrogenase; inhibitor screening; ubiquinone; antimalarial drug
• Target Audience: 一般
• Note (General): 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)
• Source: comment：fulltext; https://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=27091&item_no=1&attribute_id=70&file_no=1
• Access Restrictions: インターネット公開
• Rights (production): © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
• Related Material: http://hdl.handle.net/10069/00040957
• Related Material (DOI): 10.3390/ijms22137236
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 長崎大学 : 長崎大学学術研究成果リポジトリ