Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase
Issued Date
2026-09-05
Resource Type
ISSN
02235234
eISSN
17683254
Scopus ID
2-s2.0-105037073717
Journal Title
European Journal of Medicinal Chemistry
Volume
313
Rights Holder(s)
SCOPUS
Bibliographic Citation
European Journal of Medicinal Chemistry Vol.313 (2026)
Suggested Citation
Decharuangsilp S., Koompapong K., Arwon U., Tuyapala N., Hoarau M., Tanasugarn L., Pengon J., Talawanich Y., Saeyang T., Vanichtanankul J., Yuthavong Y., Kamchonwongpaisan S., Mahittikorn A., Kongkasuriyachai D. Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase. European Journal of Medicinal Chemistry Vol.313 (2026). doi:10.1016/j.ejmech.2026.118863 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116515
Title
Repurpose antimalarials to target Toxoplasma gondii dihydrofolate reductase thymidylate synthase
Corresponding Author(s)
Other Contributor(s)
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 (K<inf>i</inf> 1.71 nM), increased antiparasitic properties in vitro (IC<inf>50</inf> 0.44 nM), and a higher cell selectivity compared to PYR (K<inf>i</inf> 13.0 nM, IC<inf>50</inf> 410 nM) while P218 (K<inf>i</inf> 2.19 nM, IC<inf>50</inf> 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.