STRUCTURE-ACTIVITY RELATIONSHIP OF LIGANDS OF URACIL PHOSPHORIBOSYLTRANSFERASE FROM TOXOPLASMA-GONDII

One hundred compounds were evaluated as ligands of Toxoplasma gondii u racil phosphoribosyltransferase (UPRTase, EC 2.4.2.9) by examining the ir ability to inhibit this enzyme in vitro. Inhibition was quantified by determining apparent K-i values for those compounds that inhibited T. gondii UPRTase by greater than 10% at a concentration of 2 mM. Five compounds (4-thiopyridine, 2-thiopyrimidine, trithiocyanuric acid, 1- deazauracil and 2,4-dithiouracil) bound to the enzyme better than two known substrates for T. gondii UPRTase, 5-fluorouracil and emimycin, w hich have antitoxoplasmal activity (Pfefferkorn ER, Exp Parasitol 44:2 6-35, 1978; Pfefferkorn et al., Exp Parasitol 69: 129-139, 1989). In a ddition, several selected compounds were evaluated as substrates for T . gondii UPRTase, and it was found that 2,4-dithiouracil is also a sub strate for this enzyme. On the basis of these data, a structure-activi ty relationship for the binding of ligands to T. gondii UPRTase was de termined using uracil as a reference compound.