Kuyper L F, Garvey J M, Baccanari D P, Champness J N, Stammers D K, Beddell C R
Wellcome Research Laboratories, Research Triangle Park, NC 27709, USA.
Bioorg Med Chem. 1996 Apr;4(4):593-602. doi: 10.1016/0968-0896(96)00045-4.
Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR). This conformation of TMP was achieved by linking the 4-amino function to the methylene group by one- and two-carbon bridges. A pyrrolo[2,3-d]pyrimidine, a dihydro analogue, and a tetrahydropyrido[2,3-d]pyrimidine were synthesized and tested as inhibitors of DHFR. One analogue showed activity equivalent to that of TMP against DHFR from three species of bacteria. An X-ray crystal structure of this inhibitor bound to Escherichia coli DHFR was determined to evaluate the structural consequences of the conformational restriction.
抗菌剂甲氧苄啶（TMP）的构象受限类似物被设计用于模拟其与细菌二氢叶酸还原酶（DHFR）复合物中观察到的药物构象。通过一碳桥和二碳桥将4-氨基官能团与亚甲基相连，实现了TMP的这种构象。合成了一种吡咯并[2,3-d]嘧啶、一种二氢类似物和一种四氢吡啶并[2,3-d]嘧啶，并将其作为DHFR的抑制剂进行测试。一种类似物对三种细菌的DHFR显示出与TMP相当的活性。测定了该抑制剂与大肠杆菌DHFR结合的X射线晶体结构，以评估构象限制的结构后果。
