• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Design and synthesis of antifolates as inhibitors of dihydrofolate reductases in opportunistic pathogens (Pneumocystis carinii, Toxoplasma gondii).
【24h】

Design and synthesis of antifolates as inhibitors of dihydrofolate reductases in opportunistic pathogens (Pneumocystis carinii, Toxoplasma gondii).

机译：设计和合成作为机会病原体（卡氏肺孢子虫，弓形虫）中二氢叶酸还原酶抑制剂的抗叶酸剂。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The objective of this research is to develop potential agents to treat opportunistic infections associated with acquired immune deficiency syndrome (AIDS), such as Pneumocystis carinii pneumonia and toxoplasmic encephalitis. Generally, antifolate agents are used for treatments and prophylaxis of these infections. The commonly used drugs include trimethoprim, pyrimethamine, pyritrexim, and trimetrexate, all of which are inhibitors of dihydrofolate reductase (DHFR). However, all of them suffer various side effects, sometimes too severe to be tolerated by patients. More effective treatments with fewer side effects are desired for daily clinical management of AIDS patients.; Our approach of developing more effective antifolate agents was to selectively inhibit DHFR of Pneumocystis carinii and Toxoplasma gondii, an essential enzyme involved in de novo biosynthetic pathway of pathogen DNA. Based on the three-dimensional X-ray structure of the target enzyme, we designed a series of 5-arylalkyl-2,4,6-triaminopyrimidine and 5-methyl-6-arylalkyl-2,4-diamino[2,3-d]pyrimidine nonclassical antifolates with functional groups intended to interact with specific amino acid side chains at the active site of the enzyme. We hypothesized that these structural alterations would lead to selectivity of inhibition. One of the target amino acid residues was Phe69 in P. carinii DHFR. These antifolates were synthesized and tested for their inhibitory activities against DHFR of various opportunistic pathogens and their mammalian counterparts.; The two monocyclic analogues 1 and 2 showed weak activity and poor selectivity. Two of the bicyclic antifolates 3 and 5 were found to possess moderate selectivity against P. carinii DHFR. Activities of homologs of 5-arylalkyl-2,4-diaminothieno[2,3- d]pyrimidine series were compared. The bridge length of three carbon atoms was determined as optimal for potent inhibitory activity. A conformationally restrained compound (11) was also synthesized and evaluated for its activities. Based on results with 11, we proposed a possible mechanism of optimal inhibition and differential binding. Phe69 was deemed to be an attractive target for developing selectivity. A possible cooperativity of binding with NADPH may be involved in the better activity of some compounds.
机译：这项研究的目的是开发潜在的药物来治疗与获得性免疫缺陷综合症（AIDS）相关的机会性感染，例如卡氏肺孢子虫肺炎和弓形体脑炎。通常，抗叶酸剂用于治疗和预防这些感染。常用的药物包括甲氧苄氨嘧啶，乙胺嘧啶，吡虫啉和曲美酯，它们都是二氢叶酸还原酶（DHFR）的抑制剂。然而，它们所有人都有各种副作用，有时过于严重以至于患者无法忍受。对于AIDS患者的日常临床治疗，期望有副作用更少的更有效的治疗。我们开发更有效的抗叶酸药物的方法是选择性抑制卡氏肺孢子虫和弓形虫（一种参与病原体DNA从头生物合成途径的必需酶）的DHFR。基于目标酶的三维X射线结构，我们设计了一系列5-芳基烷基-2,4,6-三氨基嘧啶和5-甲基-6-芳基烷基-2,4-二氨基[2,3- d]嘧啶非经典抗叶酸剂，其具有旨在与酶的活性位点上的特定氨基酸侧链相互作用的官能团。我们假设这些结构改变将导致抑制作用的选择性。目标氨基酸残基之一是卡氏疟原虫DHFR中的Phe69。合成了这些抗叶酸药物，并测试了其对各种机会性病原体及其哺乳动物对应物的DHFR的抑制活性。两个单环类似物1和2表现出较弱的活性和较差的选择性。发现双环抗叶酸化合物3和5中的两个对卡氏疟原虫DHFR具有中等选择性。比较了5-芳基烷基-2,4-二氨基噻吩并[2,3-d]嘧啶系列同系物的活性。确定三个碳原子的桥长对于有效抑制活性是最佳的。还合成了受构象限制的化合物（11），并评价了其活性。基于11的结果，我们提出了最佳抑制和差异结合的可能机制。 Phe69被认为是开发选择性的有吸引力的目标。与NADPH结合可能的协同作用可能与某些化合物的更好活性有关。

著录项

  • 作者

    Li, Hui.;

  • 作者单位

    The University of Tennessee Health Science Center.;

  • 授予单位 The University of Tennessee Health Science Center.;
  • 学科 Chemistry Pharmaceutical.; Chemistry Organic.; Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 123 p.
  • 总页数 123
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药物化学;有机化学;药剂学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号