Synthesis and biological activity of 5-fluoro- and 5-methyl-1,3-oxazine-2,6(3H)-dione.

5-Fluoro-1,3-oxazine-2,6(3H)-dione (3-oxa-FU) was synthesized by reacting 3-oxauracil with fluoroxytrifluoromethane and decomposing the adduct in the presence of a catalytic amount of Et3N. 5-Methyl-1,3-oxazine-2,6(3H)-dione (3-oxathymine) was prepared by polyphosphoric acid catalyzed ring closure of beta-(N-ethoxycarbonylamino)-2-methacrylic acid and by treatment of citraconimide with sodium hypochlorite. As determined in vitro, 3-oxa-FU was markedly inhibitory to S. faecium (ID50 = 9 X 10(-8) M) and E. coli (ID50 = 1 X 10(-7) M) but was less active against leukemia L-1210 cells (ID50 = 1 X 10(-5) M). At 1 x 10(-4) M, 3-oxathymine was inactive in these cell systems. Inhibition of the growth of S. faecium by 3-oxa-FU was reversed competitively by the natural pyrimidines. The relatively rapid hydrolysis of the compounds in the growth media is a major factor in determining their biological effectiveness.