{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T06:49:20Z","timestamp":1783666160813,"version":"3.55.0"},"reference-count":59,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["10000284"],"award-info":[{"award-number":["10000284"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["14425718"],"award-info":[{"award-number":["14425718"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18073004"],"award-info":[{"award-number":["18073004"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18GS0314"],"award-info":[{"award-number":["18GS0314"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japanese Ministry of Education, Science, Culture, Sports and Technology","award":["16811362"],"award-info":[{"award-number":["16811362"]}]},{"name":"Japanese Ministry of Education, Science, Culture, Sports and Technology","award":["16K19114"],"award-info":[{"award-number":["16K19114"]}]},{"name":"Japanese Ministry of Education, Science, Culture, Sports and Technology","award":["19H03436"],"award-info":[{"award-number":["19H03436"]}]},{"name":"Japanese Ministry of Health and Welfare","award":["17929833"],"award-info":[{"award-number":["17929833"]}]},{"name":"Japanese Ministry of Health and Welfare","award":["20314363"],"award-info":[{"award-number":["20314363"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Plasmodium falciparum\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms22137236","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T02:59:47Z","timestamp":1625540387000},"page":"7236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"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"],"prefix":"10.3390","volume":"22","author":[{"given":"Endah Dwi","family":"Hartuti","sequence":"first","affiliation":[{"name":"Program for Nurturing Global Leaders in Tropical and Emerging Communicable Disease, Graduate School of Biomedical Science, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Laboratory for Biotechnology, Agency for the Assessment and Application of Technology, South Tangerang 15314, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8320-8485","authenticated-orcid":false,"given":"Takaya","family":"Sakura","sequence":"additional","affiliation":[{"name":"Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed S. O.","family":"Tagod","sequence":"additional","affiliation":[{"name":"School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajib","family":"Acharjee","sequence":"additional","affiliation":[{"name":"Program for Nurturing Global Leaders in Tropical and Emerging Communicable Disease, Graduate School of Biomedical Science, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Department of Parasitology, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Departement of Zoology, University of Chittagong, Chittagong 4331, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Matsuo","sequence":"additional","affiliation":[{"name":"School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan"},{"name":"Graduate School of Life Science, Kumamoto University, Kumamoto 860-0862, 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