The overall program project will test the hypothesis that a combination of thymidine and select antifolates directed at the thymidylate synthase domain of PIasmodium falciparum dihydrofolate reductase-thymidylate synthase (DHFR-TS) can be potent and safe antimalarial agents, worthy of future clinical trials in humans. Blood-stage forms of malaria parasites are completely dependent on de novo pyrimidine biosynthesis and fail to salvage preformed pyrimidines, unlike human cells. Of all the enzymes available in de novo pyrimidine biosynthesis, DHFR-TS is of particular interest. Inhibitors of the DHFR domain are proven drug targets in malaria. The PI's laboratory has previously demonstrated that one TS antifolate (1843U89) inhibits Plasmodium TS with a Ki of 1 nM and inhibits parasite proliferation with an EC50 of 70 riM. With 10 uM thymidine, mammalian cells show no toxicity to this compound, even at 10,000 times higher concentrations. Starting with this very strong lead, we will develop additional compounds that are even more potent.
The aim of this core will be to provide specialty chemicals. The ability to synthesize published antifolate molecules and key intermediates is demonstrated in this application. Hundreds of new derivatives will be synthesized as needed for the Program Project. The PI's current appointment in a large chemistry department allows Core A access to the experiences and advice of 40 tenured or tenure-track chemistry faculty, additional research scientists, about 200 chemistry graduate students, and state of the science synthesis and analytical facilities including five high-field NMRs and three MS instruments. Even though the PI has personnel interested in the biology of malaria chemotherapy, since moving to the UW Chemistry Department in 2001, he has recruited three excellent organic chemists in his lab. They will synthesize about 50 to 100 variants of TS inhibitors per year. These will be used by all three Projects to arrive at compounds and formulations that are potent antimalarials and safe for mammalian cells.
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