Mh. Iltzsch et Ee. Klenk, STRUCTURE-ACTIVITY RELATIONSHIP OF NUCLEOBASE LIGANDS OF URIDINE PHOSPHORYLASE FROM TOXOPLASMA-GONDII, Biochemical pharmacology, 46(10), 1993, pp. 1849-1858
Seventy-nine nucleobase analogs were evaluated as potential inhibitors
of Toxoplasma gondii uridine phosphorylase (UrdPase), and the apparen
t K(i) (appK(i)) values for these compounds were determined. Based on
the inhibition data, a structure-activity relationship for the binding
of nucleobase analogs to the enzyme was formulated, using uracil as a
reference compound. Two compounds were identified as very potent inhi
bitors of T. gondii UrdPase, 5-benzyloxybenzylbarbituric acid and 5-be
nzyloxybenzyluracil, which had appK(i) values of 0.32 and 2.5 muM, res
pectively. A comparison of the results from the present study, with si
milar studies on mammalian UrdPase and thymidine phosphorylase (dThdPa
se) (Niedzwicki et al., Biochem Pharmacol 32: 399-415, 1993) revealed
that there are both similarities and differences between the catalytic
site of T. gondii UrdPase and the catalytic sites of the mammalian en
zymes with respect to binding of uracil analogs. One compound, 6-benzy
l-2-thiouracil, was identified as a potent, specific inhibitor (appK(i
) = 14 muM) of T. gondii UrdPase, relative to mammalian UrdPase and dT
hdPase.