Synthesis of branched 9-[2-(2-phosphonoethoxy)ethyl]purines as a new class of acyclic nucleoside phosphonates which inhibit Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase.
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.
Hocková
Dana
D
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, Prague 6 166 10, Czech Republic. lasice@uochb.cas.cz
Holý
Antonín
A
Masojídková
Milena
M
Keough
Dianne T
DT
de Jersey
John
J
Guddat
Luke W
LW
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D063065:Organophosphonates / Q000737:chemistry; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011687:Purines; D010430:Pentosyltransferases; C083867:hypoxanthine-guanine-xanthine phosphoribosyltransferase