Li R L, Poe M
Department of Medicinal Chemistry, Beijing Medical University, China.
J Med Chem. 1988 Feb;31(2):366-70. doi: 10.1021/jm00397a017.
Quantitative structure-activity relationships for the inhibition of Escherichia coli (MB 1428) dihydrofolate reductase (DHFR) by 61 5-(substituted benzyl)-2,4-diaminopyrimidines are reported and analyzed. The 61 compounds include 17 congeners whose activities have not been previously reported, five of which have a 5'-substituent larger than a methoxy group. The correlation equations indicated that the molar refractivity (MR) values of the 5'-substituent, just as with the 3'- and 4'-substituents, contributed maximally at the value of 0.79 with no increment of binding for compounds with MR larger than 0.79 (which corresponds to a 5'-methoxy substitution). This experimental result is in agreement with the crystal structure of the Escherichia coli DHFR-trimethoprim complex, which shows a reasonably large trimethoprim-binding site. The inhibition of E. coli (MB 1428) DHFR by nine of the 17 new benzylpyrimidines is at lower concentrations than for trimethoprim. However, all 17 are much less potent than trimethoprim in inhibition of growth of E. coli (1515).
报道并分析了61种5-(取代苄基)-2,4-二氨基嘧啶对大肠杆菌(MB 1428)二氢叶酸还原酶(DHFR)抑制作用的定量构效关系。这61种化合物包括17种同系物，其活性此前未被报道，其中5种的5'-取代基大于甲氧基。相关方程表明，5'-取代基的摩尔折射率(MR)值，与3'-和4'-取代基一样，在0.79时贡献最大，对于MR大于0.79的化合物(对应于5'-甲氧基取代)，结合力没有增加。这一实验结果与大肠杆菌DHFR-甲氧苄啶复合物的晶体结构一致，该结构显示出一个相当大的甲氧苄啶结合位点。17种新苄基嘧啶中的9种对大肠杆菌(MB 1428)DHFR的抑制作用浓度低于甲氧苄啶。然而，在抑制大肠杆菌(1515)生长方面，所有17种化合物的效力都远低于甲氧苄啶。
