Design, synthesis, and biological evaluation of homologous phosphonic acids and sulfonic acids as inhibitors of lumazine synthase

Three phosphonic acid inhibitors of lumazine synthase were synthesized in which the phosphorus atom was separated from the pyrimidinedione ring by polymethylene linker chains containing four, five, and six carbon atoms. Three analogous sulfonic acids were also synthesized. The inhibitors were designed as metabolically stable analogues of a hypothetical intermediate in the reaction catalyzed by lumazine synthase, and the design process was supported by the results of computer graphics molecular modeling of the inhibitors within the active site of the enzyme. The most potent of the new inhibitors, 6-(6-D-ribitylamino-2,4-dihydroxypyrimidine-5-yl)-1-hexylphosphonic acid, inhibited recombinant lumazine synthase beta(60) capsids of Bacillus subtilis with a K-i of 130 mu M, making it the most potent inhibitor of lumazine synthase reported to date.