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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

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...

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Autores principales: Hartuti, Endah Dwi, Sakura, Takaya, Tagod, Mohammed S. O., Yoshida, Eri, Wang, Xinying, Mochizuki, Kota, Acharjee, Rajib, Matsuo, Yuichi, Tokumasu, Fuyuki, Mori, Mihoko, Waluyo, Danang, Shiomi, Kazuro, Nozaki, Tomoyoshi, Hamano, Shinjiro, Shiba, Tomoo, Kita, Kiyoshi, Inaoka, Daniel Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268581/
https://www.ncbi.nlm.nih.gov/pubmed/34281290
http://dx.doi.org/10.3390/ijms22137236
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author Hartuti, Endah Dwi
Sakura, Takaya
Tagod, Mohammed S. O.
Yoshida, Eri
Wang, Xinying
Mochizuki, Kota
Acharjee, Rajib
Matsuo, Yuichi
Tokumasu, Fuyuki
Mori, Mihoko
Waluyo, Danang
Shiomi, Kazuro
Nozaki, Tomoyoshi
Hamano, Shinjiro
Shiba, Tomoo
Kita, Kiyoshi
Inaoka, Daniel Ken
author_facet Hartuti, Endah Dwi
Sakura, Takaya
Tagod, Mohammed S. O.
Yoshida, Eri
Wang, Xinying
Mochizuki, Kota
Acharjee, Rajib
Matsuo, Yuichi
Tokumasu, Fuyuki
Mori, Mihoko
Waluyo, Danang
Shiomi, Kazuro
Nozaki, Tomoyoshi
Hamano, Shinjiro
Shiba, Tomoo
Kita, Kiyoshi
Inaoka, Daniel Ken
author_sort Hartuti, Endah Dwi
collection PubMed
description 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.
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spelling pubmed-82685812021-07-10 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 Hartuti, Endah Dwi Sakura, Takaya Tagod, Mohammed S. O. Yoshida, Eri Wang, Xinying Mochizuki, Kota Acharjee, Rajib Matsuo, Yuichi Tokumasu, Fuyuki Mori, Mihoko Waluyo, Danang Shiomi, Kazuro Nozaki, Tomoyoshi Hamano, Shinjiro Shiba, Tomoo Kita, Kiyoshi Inaoka, Daniel Ken Int J Mol Sci Article 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. MDPI 2021-07-05 /pmc/articles/PMC8268581/ /pubmed/34281290 http://dx.doi.org/10.3390/ijms22137236 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
Hartuti, Endah Dwi
Sakura, Takaya
Tagod, Mohammed S. O.
Yoshida, Eri
Wang, Xinying
Mochizuki, Kota
Acharjee, Rajib
Matsuo, Yuichi
Tokumasu, Fuyuki
Mori, Mihoko
Waluyo, Danang
Shiomi, Kazuro
Nozaki, Tomoyoshi
Hamano, Shinjiro
Shiba, Tomoo
Kita, Kiyoshi
Inaoka, Daniel Ken
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268581/
https://www.ncbi.nlm.nih.gov/pubmed/34281290
http://dx.doi.org/10.3390/ijms22137236
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