Relation of structure to the inhibitory activity of purines against urate oxidase

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Abstract
The inhibitory effect of purines and related heterocyclic compounds on the degradation of uric acid was used to measure their affinity for urate oxidase. Of the three oxygen atoms of uric acid, that of the 2-carbonyl group possesses the greatest binding power for the active centre. Replacement of this oxygen atom by sulphur greatly diminishes the inhibitory activity. Combination of a 2-carbonyl group with sulphur at C-6 enhances inhibitory activity considerably. In certain purine derivatives, a 6-methylmercapto substituent is more effective than a 6-thiocarbonyl group. 2,8-Dihydroxy-6-methylmercaptopurine is the most potent inhibitor of urate oxidase known so far. Replacement of the imidazole moiety of the purine ring by triazole enhances affinity, whereas introduction of the pyrazine ring, as in pteridines, greatly decreases it. Free imino groups are essential for the attachment of purines to urate oxidase, as N-methylation weakens or abolishes the inhibitory effect. On the other hand, in 2-thiopurines methylation at N-3 increases the inhibitory power.