Abstract
The malarial parasite Plasmodium falciparum (Pf) lacks the de novo pathway and relies on the salvage enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), for the synthesis of the 6-oxopurine nucleoside monophosphates. Specific acyclic nucleoside phosphonates (ANPs) inhibit PfHGXPRT and possess anti-plasmodial activity. Two series of novel branched ANPs derived from 9-[2-(2-phosphonoethoxy)ethyl]purines were synthesized to investigate their inhibition of PfHGXPRT and human HGPRT. The best inhibitor of PfHGXPRT has a K(i) of 1 microM. The data showed that both the position and nature of the hydrophobic substituent change the potency and selectivity of the ANPs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Catalytic Domain
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Computer Simulation
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Organophosphonates / chemistry
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Pentosyltransferases / antagonists & inhibitors*
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Pentosyltransferases / metabolism
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Plasmodium falciparum / enzymology*
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Purines / chemical synthesis*
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Purines / chemistry
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Purines / pharmacology
Substances
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Antimalarials
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Enzyme Inhibitors
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Organophosphonates
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Purines
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Pentosyltransferases
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hypoxanthine-guanine-xanthine phosphoribosyltransferase