THE SYNTHESIS OF DIHYDROFOLATE REDUCTASE INHIBITOR 2,4-DIAMINO-5-SUBSTITUTED-BENZYLPYRIMIDINES AND THEIR INHIBITION ON L. CASEI DHFR AND CHICKEN LIVER DHFR

Eighteen 5-(substituted benzyl)-2,4-diamino-pyrimidine with groups of various sizes on the benzene ring were designed and synthesized for investigating the inhibition of dihydrofolate reductase (DHFR). The pyrimidines were prepared by the condensation of 2-benzyl-3-anilinoacrylonitriles and guanidine hydrochloride in the absolute alcohol of sodium alkoxide base catalysed condensation of the substituted benzaldehydes with 2-bnzyl-3-morpholinoacrylonitrles, which were converted to the aniline derivatives on treatment with aniline hydrochloride in 2-propanol. Substituted benzaldehyde were synthesized from the corresponding benzoic acid esters by converting to hydrazides, which were then oxidized by potassium ferrocyanide. The physical properties of 39 intermediates are reported.Inhibitory activity on chicken liver and Lacatobacillus Casei dihydrofolate reduetase by the pyrimidines were reported. Struetureactivity relations are briefly discussed. Substituents which showed greater selectivity are: 3'-OH, 4'-OCHs; 3'-OCH₃, 4-OC₂H₄OCH₃.