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- W3023158848 abstract "The malarial parasite, Plasmodium falciparum, synthesises pyrimidines and folate de novo and is unable to synthesise pyrimidines via the alternative salvage pathway from preformed uridine or cytidine (Scheibel and Sherman, 1988). By contrast, purines are not synthesised de novo and must be salvaged from preformed purines such as adenosine which is readily available within the human erythrocyte (Szabados et al., 1996). Drug resistance has become a major problem for the treatment of malaria and many potential antagonists of nucleotide and folate biosynthesis have been tested for selective toxicity against the parasite. Because the parasite only has the de novo pyrimidine pathway and humans have both the de novo and salvage pathways, inhibitors of the de novo pyrimidine pathway could be effective antimalarial drugs. We have synthesised several potent inhibitors of the enzyme dihydroorotase (CA-asp→ DHO, eq 1; Christopherson et al, 1989), 6-L-thiodihydroorotate (TDHO) blocks de novo pyrimidine biosynthesis in parasites, inducing accumulation of CA-asp and depletion of UTP and CTP (Seymour et al., 1994). Atovaquone blocks the respiratory chain of malarial mitochondria at Complex III, leading to inhibition of dihydroorotate dehydrogena&e (DHO→ Oro, eq 1) and consequent accumulation of DHO and CA-asp (Seymour et al. 1994). Pyrazofurin as the nucleoside 5′-mo-nophosphate derivative, inhibits OMP decarboxylase (OMP→ UMP, eq 1) with accumulation of orotidine and Oro in cells (Seymour et al., 1994). 5-Fluoroorotate (FOro) is a potent inhibitor of the growth of P. falciparum and has an ID50 value of 42 nM while 5-fluorouracil (FUra) is far less toxic with an ID50 of 5.2 μM (Queen et al., 1990). FOro is converted to FUTP which may inhibit the malarial carbamyl phosphate synthetase (Seymour et al., 1994)." @default.
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- W3023158848 date "1997-04-01" @default.
- W3023158848 modified "2023-09-27" @default.
- W3023158848 title "Pyrimidine antagonists and antifolates as antimalarial drugs" @default.
- W3023158848 doi "https://doi.org/10.1016/s0009-9120(97)87662-x" @default.
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