[摘要]：Several 7-deaza-6-benzylthioinosine analogs with varied substituents on arom. ring were synthesized and evaluated against Toxoplasma gondii adenosine kinase (EC.2.7.1.20). Structure-activity relationships indicated that the nitrogen atom at the 7-position does not appear to be a crit. structural requirement. Mol. modeling reveals that the 7-deazapurine motif provided flexibility to the 6-benzylthio group as a result of the absence of H-bonding between N7 and Thr140. This flexibility allowed better fitting of the 6-benzylthio group into the hydrophobic pocket of the enzyme at the 6-position. In general, single substitutions at the para or meta position enhanced binding. On the other hand, single substitutions at the ortho position led to the loss of binding affinity. The most potent compds., 7-deaza-p-cyano-6-benzylthioinosine I (R = CN) (IC50 = 5.3 mM) and 7-deaza-p-methoxy-6-benzylthioinosine I (R = OCH3) (IC50 = 4.6 mM), were evaluated in cell culture to delineate their selective toxicity.
