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

Abstract

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.

A Mild and Efficient Copper-Mediated N-Arylation of 6-Azauracil with Corresponding Boronic Acids and their Antibacterial Activity

“…They are also used as a fungicide [6], chemotherapeutic agents for psoriasis [7], for polyarthritis [8] and for polycythemia vera [9]. It has been reported that 1-N position of 6-azauracil is served as the best location to place a substituent to mimic the size and shape of the natural nucleoside [10]. Attachment of substituted phenyl side chain at N-1 of 6-azauracil causes increasing its potency, which was related in part to the acidity of the imide hydrogen.…”

An Optimized Synthesis, Molecular Structure and Characterization of Benzylic Derivatives of 1,2,4-Triazin-3,5(2H,4H)-dione

“…6-Azauracil and its derivatives form an important class of heteroaromatic compounds with various interesting biochemical properties [ 1 ]. Among these derivatives the 2-benzyl-1,2,4-triazin-3,5(2 H ,4 H )-dione has showed anticoccidial activity [ 25 ] and property of aldose reductase inhibitor [ 26 ]. Banavara [ 25 ] reported the product yields were in 10–40% range in synthesis 2-substituted, 4-substituted, or symmetrically 2,4-disubstituted 1,2,4-triazin-3,5(2 H ,4 H )-dione compounds, and the yield of synthesis of unsymmetrically 2,4-disubstituted compounds were showed in 20–60%.…”

“…Among these derivatives the 2-benzyl-1,2,4-triazin-3,5(2 H ,4 H )-dione has showed anticoccidial activity [ 25 ] and property of aldose reductase inhibitor [ 26 ]. Banavara [ 25 ] reported the product yields were in 10–40% range in synthesis 2-substituted, 4-substituted, or symmetrically 2,4-disubstituted 1,2,4-triazin-3,5(2 H ,4 H )-dione compounds, and the yield of synthesis of unsymmetrically 2,4-disubstituted compounds were showed in 20–60%. In our past studies on acyclonucleosides synthesis the site of glycosylation was established at the N-2 position of the 2-substituted products of 1,2,4-triazin-3,5(2 H ,4 H )-dione, based on the comparison of the UV spectra and identified by 1 H- 13 C heteronuclear correlation (HETCOR) NMR experiments [ 27 , 28 , 29 ].…”