{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:26:45Z","timestamp":1788791205486,"version":"build-2803163510"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Australian Government Research Training Program"},{"name":"German Academic Research Exchange"},{"name":"K.M. Medhealth"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,12,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Thiamine is metabolized into thiamine pyrophosphate (TPP), an essential enzyme cofactor. Previous work has shown that oxythiamine, a thiamine analog, is metabolized by thiamine pyrophosphokinase (TPK) into oxythiamine pyrophosphate within the malaria parasite\n              <jats:italic>Plasmodium falciparum<\/jats:italic>\n              and then inhibits TPP-dependent enzymes, killing the parasite\n              <jats:italic>in vitro<\/jats:italic>\n              and\n              <jats:italic>in vivo<\/jats:italic>\n              . To identify a more potent antiplasmodial thiamine analog, 11 commercially available compounds were tested against\n              <jats:italic>P. falciparum<\/jats:italic>\n              and\n              <jats:italic>P. knowlesi<\/jats:italic>\n              . Five active compounds were identified, but only N3-pyridyl thiamine (N3PT), a potent transketolase inhibitor and candidate anticancer lead compound, was found to suppress\n              <jats:italic>P. falciparum<\/jats:italic>\n              proliferation with an IC\n              <jats:sub>50<\/jats:sub>\n              value 10-fold lower than that of oxythiamine. N3PT was active against\n              <jats:italic>P. knowlesi<\/jats:italic>\n              and was &gt;17 times less toxic to human fibroblasts, as compared to oxythiamine. Increasing the extracellular thiamine concentration reduced the antiplasmodial activity of N3PT, consistent with N3PT competing with thiamine\/TPP. A transgenic\n              <jats:italic>P. falciparum<\/jats:italic>\n              line overexpressing TPK was found to be hypersensitized to N3PT. Docking studies showed an almost identical binding mode in TPK between thiamine and N3PT. Furthermore, we show that [\n              <jats:sup>3<\/jats:sup>\n              H]thiamine accumulation, resulting from a combination of transport and metabolism, in isolated parasites is reduced by N3PT. Treatment of\n              <jats:italic>P. berghei<\/jats:italic>\n              -infected mice with 200 mg\/kg\/day N3PT reduced their parasitemia, prolonged their time to malaria symptoms, and appeared to be non-toxic to mice. Collectively, our studies are consistent with N3PT competing with thiamine for TPK binding and inhibiting parasite proliferation by reducing TPP production, and\/or being converted into a TPP antimetabolite that inhibits TPP-dependent enzymes.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01096-24","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:00:38Z","timestamp":1730206838000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Identification and characterization of thiamine analogs with antiplasmodial activity"],"prefix":"10.1128","volume":"68","author":[{"given":"Imam","family":"Fathoni","sequence":"first","affiliation":[{"name":"Research School of Biology, The Australian National University","place":["Canberra, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence C. 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