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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8268581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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