Chan J H, Roth B
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
J Med Chem. 1991 Feb;34(2):550-5. doi: 10.1021/jm00106a011.
A conformationally restricted analogue of trimethoprim (1a) has been prepared by connecting the ortho position of the benzene ring to the methylene linkage with two methylene groups, thus forming a dihydroindene derivative (2b). The chemistry involved the condensation of barbituric acid with an indanone derivative, followed by a three-step conversion to a 2,4-diaminopyrimidine. The S isomer of 2b was found to have a minimum-energy conformation very similar to that of 1a when bound to Escherichia coli dihydrofolate reductase, in contrast to that of 1a in vertebrate DHFR. Theoretically such a derivative might have increased specificity and activity against the bacterial enzyme. Molecular modeling experiments suggested that the actual decreased activity was due to crowding in the enzyme, caused by the extra atoms needed to restrict the conformation.
通过用两个亚甲基将苯环的邻位连接到亚甲基链上，制备了一种构象受限的甲氧苄啶类似物（1a），从而形成了一种二氢茚衍生物（2b）。该化学过程涉及巴比妥酸与茚满酮衍生物的缩合，随后经过三步转化为2,4-二氨基嘧啶。发现2b的S异构体在与大肠杆菌二氢叶酸还原酶结合时具有与1a非常相似的最低能量构象，这与1a在脊椎动物二氢叶酸还原酶中的情况形成对比。理论上，这样的衍生物可能对细菌酶具有更高的特异性和活性。分子模拟实验表明，实际活性降低是由于限制构象所需的额外原子导致酶中拥挤所致。
