Fnm. Naguib et al., STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE BINDING OF LIGANDS TO XANTHINE OR GUANINE PHOSPHORIBOSYL TRANSFERASE FROM TOXOPLASMA-GONDII, Biochemical pharmacology, 50(10), 1995, pp. 1685-1693
Preliminary characterization of Toxoplasma gondii phosphoribosyltransf
erase activity towards purine nucleobases indicates that there are at
least two enzymes present in these parasites. One enzyme uses hypoxant
hine, guanine, and xanthine as substrates, while a second enzyme uses
only adenine. Furthermore, competition experiments using the four poss
ible substrates suggest that there may be a third enzyme that uses xan
thine. Therefore, sixty-eight purine analogues and thirteen related de
rivatives were evaluated as ligands of T. gondii phosphoribosyltransfe
rase, using xanthine or guanine as substrates, by examining their abil
ity to inhibit these reactions in vitro. Inhibition was quantified by
determining apparent K-i values for compounds that inhibited these act
ivities by greater than 10% at a concentration of 0.9 mM. On the basis
of these data, a structure-activity relationship for the binding of l
igands to these enzymes was formulated using hypoxanthine (6-oxopurine
) as a reference compound. It was concluded that the following structu
ral features of purine analogues are required or strongly preferred fo
r binding to both enzymes: (1) a pyrrole-type nitrogen (lactam form) a
t the 1-position; (2) a methine (=CH-), a pyridine type nitrogen (=N-)
, or an exocyclic amino or oxo group at the 2-position; (3) no exocycl
ic substituents at the 3-position; (4) an exocyclic oxo or thio group
in the one or thione tautomeric form at the 6-position; (5) a pyridine
-type nitrogen (=N-) or a methine group at the 7-position; (6) a methi
ne group at the 8-position; (7) a pyrrole-type nitrogen or a carbon at
the 9-position; and (8) no exocyclic substituents at the 9-position.
These findings provide the basis for the rational design of additional
ligands of hypoxanthine, guanine, and xanthine phosphoribosyltransfer
ase activities in T, gondii.