STRUCTURE-ACTIVITY RELATIONSHIP OF NUCLEOBASE LIGANDS OF URIDINE PHOSPHORYLASE FROM TOXOPLASMA-GONDII

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.