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Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo

Mui, Ernest J and Schiehser, Guy A and Milhous, Wilbur K and Hsu, Honghue and Roberts, Craig W and Kirisits, Michael and Muench, Stephen and Rice, David and Dubey, J P and Fowble, Joseph W and Rathod, Pradipsinh K and Queener, Sherry F and Liu, Susan R and Jacobus, David P and McLeod, Rima (2008) Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. PLOS Neglected Tropical Diseases, 2 (3). ISSN 1935-2727

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Abstract

Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3′(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3′-(2-chloro-4-trifluoromethoxyphenyl​oxy)propyl oxy)- 5-isopropylbiguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056) are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines. Toxoplasmosis is a neglected tropical disease, an emerging disease as well as a significant problem in developed countries causing a substantial health burden. Better medicines with less toxicity are greatly needed. Herein, we found that a novel triazine currently being advanced to clinical trials for malaria, JPC-2067-B, is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056) are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. Toxicology data are presented. JPC-2056/JPC-2067-B have potential to be more effective and less toxic treatments for toxoplasmosis than currently available medicines.