Dihydrofolate Reductase Inhibitors
Dihydrofolate Reductase Inhibitors
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二氢叶酸还原酶抑制剂
DOI：
10.1007/978-3-642-69254-3_5
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发表时间：
1984
影响因子：
1.5
通讯作者：
R. Ferone
中科院分区：
文献类型：
--
作者：
R. Ferone
在探索具有抗疟活性的苯胺基嘧啶的结构变化时，帝国化学工业的一个小组发现，合成为开环类似物的某些双胍类化合物对鸡疟原虫感染具有良好的活性（Curd等人，1945年）。后来，Burroughs Wellcome的一个小组在测试各种类型的嘧啶作为核酸合成抑制剂时指出，最具活性的双胍类药物氯胍（氯胍）与叶酸拮抗剂2，4-二氨基-5-芳氧基嘧啶之间存在形式上的结构相似性（Falco et al 1949）。此后不久，发现氯胍代谢环化为二氢三嗪，这是一种活性代谢物，是叶酸拮抗剂（Carrington et al. 1951）。最后，研究表明，二氨基嘧啶、乙胺嘧啶和二氢三嗪、环胍具有共同的作用位点--对疟疾二氢叶酸还原酶的活性具有强大的选择性抑制作用（Ferone等人，1969年）。因此，无意中合成为前药的一种化合物和来自非靶向抗代谢物合成程序的另一种化合物一起作为化学治疗利用同功能酶的物种差异的主要例子。这些药物在预防和抑制人类疟疾方面已经历了30年的大规模使用。
While exploring structural variations of anilinopyrimidines with antimalarial activity, a group at Imperial Chemical Industries found that certain biguanides synthesised as ring-opened analogues possessed good activity against Plasmodium gallinaceum infections in chicks (Curd et al. 1945). Later, a group at Burroughs Wellcome who were testing various types of pyrimidines as inhibitors of nucleic acid synthesis pointed out a formal structural analogy between the most active of the biguanides, proguanil (chlorguanide), and a 2,4-diamino-5-aryloxypyrimidine which was a folic acid antagonist (Falco et al 1949). Soon after this, it was discovered that proguanil is cyclised metabolically to a dihydrotriazine, an active metabolite which is a folic acid antagonist (Carrington et al. 1951). Eventually, it was shown that the diaminopyrimidine, pyrimethamine, and the dihydrotriazine, cycloguanil, share a common locus of action — the powerful, selective inhibition of the activity of malarial dihydrofolate reductase (Ferone et al. 1969). Thus, one compound which was inadvertently synthesised as a prodrug and another which derived from a programme of synthesis of untargeted antimetabolites, together stand as prime examples of chemotherapeutic exploitation of species differences of isofunctional enzymes. These drugs have experienced 3 decades of widescale use for the prophylaxis and suppression of human malaria.