Anticoccidial derivatives of 6-azauracil. 5. Potentiation by benzophenone side chains.

Attachment of p-benzophenone side chains at N1 was found to be one of the most effective modifications for enhancing the potency of 6-azauracil against a broad spectrum of coccidia in chickens. Compound 20 was about 1000-fold more potent than 6-azauracil. Structure-activity relationships paralleled those found in a previously reported series of related analogues containing diphenyl sulfide and sulfone side chains. Drug metabolism studies showed the ketones to be reduced rapidly to carbinols, which are the prevalent species in vivo.

Anticoccidial derivatives of 6-azauracil. 4. A 1000-fold enhancement of potency by phenyl sulfide and phenyl sulfone side chains.

We report further progress in exploiting our earlier discovery that the anticoccidial activity of 6-azauracil increases markedly when appropriately substituted benzyl or phenyl groups are attached at N-1. With guidance from previous structure-activity relationships and a multiple linear regression analysis, 6-azauracils containing phenyl sulfone or phenyl sulfide side chains were prepared. These prevented a broad spectrum of coccidial infections in chickens at minimum inhibitory concentrations by weight in feed as low as 0.25 ppm, a 4000-fold increase in potency over 6-azauracil, and had shorter plasma half-lives than earlier potent analogues. Sulfides were more potent than sulfones, although they were oxidized rapidly to sulfones in vivo.

Anticoccidial derivatives of 6-azauracil. 3. Synthesis, high activity, and short plasma half-life of 1-phenyl-6-azauracils containing sulfonamide substituents.

A series of 1-phenyl-6-azauracils containing sulfonamide substituents was prepared. In contrast to previous 1-phenyl-6-azauracils, some of these sulfonamides combine high activity against Eimeria tenella infections in chickens with a very rapid rate of clearance from plasma. Most active was 1-[3'-chloro-5'-methyl-4'-(morpholinylsulfonyl)phenyl]-6-azauracil, with a minimum effective concentration in feed of about 10 ppm.

Anticoccidial derivatives of 6-azauracil. 2. High potency and long plasma life of N1-phenyl structures.

Attachment of substituted phenyl side chains at N1 of 6-azauracil caused striking increases in plasma life and anticoccidial potency. The increases were related in part to the acidity of the imide hydrogen. Maximum effects were shown by phenyl rings substituted in both meta positions by compact, electron-withdrawing, lipophilic substituents, as in 1-(3',5'-dichlorophenyl)-6-azauracil, which had plasma half-life of 160 h and a potency 250-fold greater than that of 6-azauracil.

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

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 derivaties, 1-(3-cyanobenzyl)-6-azauracil, is about 16 times as potent as 6-azauracil.