2. Academic Validation
  3. Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase

Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase

  • Eur J Med Chem. 2026 Sep 5:313:118863. doi: 10.1016/j.ejmech.2026.118863.
Sasithorn Decharuangsilp 1,  Khuanchai Koompapong 2,  Uthai Arwon 1,  Nongnaput Tuyapala 3,  Marie Hoarau 1,  Lokachet Tanasugarn 4,  Jutharat Pengon 1,  Yuwadee Talawanich 1,  Thanaya Saeyang 1,  Jarunee Vanichtanankul 1,  Yongyuth Yuthavong 1,  Sumalee Kamchonwongpaisan 1,  Aongart Mahittikorn 5,  Darin Kongkasuriyachai 6
Affiliations

Affiliations

  • 1 National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Khlong Nueng, Khlong Luang, Pathum Thani, 12120, Thailand.
  • 2 Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, 10400, Thailand.
  • 3 National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Khlong Nueng, Khlong Luang, Pathum Thani, 12120, Thailand.
  • 4 Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, 10400, Thailand.
  • 5 Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, 10400, Thailand. Electronic address: aongart.mah@mahidol.ac.th.
  • 6 National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Khlong Nueng, Khlong Luang, Pathum Thani, 12120, Thailand. Electronic address: darin@biotec.or.th.
PMID: 42060965 DOI: 10.1016/j.ejmech.2026.118863
Abstract

Toxoplasma gondii is an obligate intracellular blood and tissue protozoan Parasite that infects up to a third of the population worldwide. Several antimalarial drugs, in particular pyrimethamine (PYR), have been used for decades to treat toxoplasmosis. Here, the clinical candidate P218, a potent inhibitor of Plasmodium falciparum dihydrofolate reductase (PfDHFR), and a series of flexible diaminopyrimidine butyrolactone analogues were identified as potent T. gondii dihydrofolate reductase (TgDHFR) inhibitors. The most promising butyrolactone analogue, LA4, displayed an improved TgDHFR inhibition (Ki 1.71 nM), increased antiparasitic properties in vitro (IC50 0.44 nM), and a higher cell selectivity compared to PYR (Ki 13.0 nM, IC50 410 nM) while P218 (Ki 2.19 nM, IC50 370 nM) presented an improved activity with comparable cell selectivity to PYR. The in vivo results against T. gondii RH strain-infected mice showed that P218 reduced parasitic burden in blood whereas LA4 decreased Parasite load in peritoneal fluid and blood with an extended mice survival. These findings position butyrolactone LA4 as a new potential for the treatment of acute toxoplasmosis.

Keywords

Antifolate; Antimalarial; DHFR inhibitor; Flexible diaminopyrimidine; Toxoplasma gondii; Toxoplasmosis.

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