Anticoccidial derivatives of 6 azauracil. I. Enhancement of activity by benzylation of nitrogen 1. Observations on the design of nucleotide analogues in chemotherapy

Article abstract of DOI:10.1021/jm00214a003

Benzylation of 6-azauracil at N-1 (which corresponds to the point of attachment of the ribose phosphate unit in pyrimidine nucleotides) has been found to augment its anticoccidial activity fourfold. The high potency of 1-benzyl-6-azauracil is ascribed to a combination of intrinsic activity, efficient oral absorption, and a moderate rate of excretion. Metabolism experiments using 1-benzyl-6-azauracil labeled with ¹⁴C in the heterocycle and (separately) in the side chain showed that, in the drug accounted for, no cleavage had occurred. Additional activity increases were achieved by introducing small, electron-withdrawing substituents in the meta and/or para position(s) of the benzyl group. One of the most active derivatives, 1-(3-cyanobenzyl)-6-azauracil, is about 16 times as potent as 6-azauracil.