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本文报道了59个5-取代苄基-2,4-二氨基嘧啶(1)对乳酪菌(L.casei)二氢叶酸还原酶(DHFR)及鸡肝DHFR产生50％抑制作用的摩尔浓度(log 1/ki _app),并采用Hansch方法分别研究了(1)对L.caseiDHFR及鸡肝DHFR抑制作用的定量构效关系(QSAR)。(1)对L.casei DHFR的抑制作用与(1)的苯环上3,4-取代基的限制数值的立体参数Vw′_(3,4)有显著的关系(Vw为取代基的Van der waals体积)。Vw′_(3,4)以2×0.304为最大值,即每个位置上的取代基的Vander waals体积大于0.304时,仍以0.304计算,即假设取代基大于0.304(甲氧基的Vw为0.304)的部分不与酶的活性部位相接触。(1)对L.casei DHFR的抑制作用还与3,4-位取代基的疏水性参数(π)成kubiry双线性相关,而以π_(3,4)=1.00为最大点。取代基的共轭电性参数(σ_(R))与化合物对L.casei DHFR的抑制作用呈负相关。QSAR的研究表明(1)的苯环上代以Vander waals体积等于或大于2×0.304同时π_(3,4)=1.00及具有给电子效应的取代基时,将对L.casei DHFR具有很强的抑制作用。5-位上即使代以较大的取代基时,其立体效应及疏水性对L.casei DHFR的抑制作用也没有影响。这可能是由于L.casei DHFR与5-取代基相接触的活性部位的空间较小,当5-取代基与酶的活性部位相结合时将伴随着去水合作用,因此抵销?
In this paper, we reported the molar concentrations of 59 5-substituted benzyl-2,4-diaminopyrimidines (1) in 50% inhibition of L.casei dihydrofolate reductase (DHFR) and chicken liver DHFR log 1 / ki _app). The quantitative structure-activity relationship (QSAR) of (1) inhibition of L.casei DHFR and chicken liver DHFR were studied by Hansch method. (1) The inhibition of L.casei DHFR has a significant relationship with the stereoscopic parameter Vw ’_ (3,4) for the limit value of 3,4-substituent on the benzene ring of (1) (Vw is the substituent of Van der waals volume). Vw ’_ (3,4) is 2 × 0.304 maximal, ie, the Vander waals volume of the substituent at each position is greater than 0.304, which is still 0.304, assuming that the substituent is greater than 0.304 (Vw for methoxy 0.304) does not come into contact with the active site of the enzyme. (1) The inhibition of L.casei DHFR is also related to the kubiry bilinearity of the hydrophobic parameter (π) at the 3,4-substituent, while π_ (3,4) = 1.00 is the maximum. The conjugate electrical parameters (σ_ (R)) of the substituents were negatively correlated with the inhibitory effect of the compounds on L.casei DHFR. QSAR studies have shown that (1) the benzene ring on behalf of the generation of Vander waals volume equal to or greater than 2 × 0.304 while π_ (3,4) = 1.00 and have electronic effects of the substituent, will L.casei DHFR has a strong Inhibition. The steric and hydrophobic effects on the inhibition of L.casei DHFR were not affected by the substitution of a larger substituent at the 5-position. This may be due to the small space available for the active site of L.casei DHFR to contact the 5-substituent, which would be counteracted when the 5-substituent is combined with the active site of the enzyme for dehydration.