2,4-二氨基-5-取代苄基嘧啶类化合物的合成及其抑酶活性

本文设计并合成了18个在苄基上带有不同体积取代基的2,4-二氨基-5-取代苄基嘧啶类化合物。测定了这些化合物对乳酪菌二氢叶酸还原酶及对鸡肝二氢叶酸还原酶的表观50%抑制作用。其中2,4-二氨基-5-(3′-羟基-4′-甲氧基)苄基、2,4-二氨基-5-(3′-甲氧基-4′-甲氧乙氧基)苄基嘧啶对上述二氢叶酸还原酶(DHFR)的选择性较好。

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.