• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease
【24h】

Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease

机译：吡唑 - 咪唑啉和新吡唑 - 四氢嘧啶杂交物作为棘抗病的有前途化学治疗剂的合成，结构 - 活性关系和胰腈灭绝活性

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

Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：随着潜在的候选药物临床试验失败，药物治疗仍然是一个重大挑战。目前可用的药物有限，诱导严重的副作用。因此，迫切需要发现新药的抗击抗菌病。这里，我们合成并评估了吡唑 - 咪唑啉（1A-I）和吡唑 - 四氢嘧啶（2A-1）衍生物对相关临床形式的葡萄球菌瘤Cruzi的生物学效果。在体外主要活性化合物的结构 - 活性关系（SAR），药物目标搜索，物理化学和呼吸特性也被评估在硅藻中。吡唑衍生物在Vero细胞中没有毒性，也没有心脏毒性。表型筛选揭示了两种二氯化的吡唑 - 咪唑啉衍生物（1C和1D），其胰蛋白酶活性高于苯并咪唑（BZ）对抗胰蛋白酶的蛋白酶;这些也是对抗细胞内amastigotes最有效的化合物。在吡唑化合物中用四氢嘧啶替代咪唑啉完全废除了2系列（A-I）衍生物的胰蛋白酶活性。化合物的物理化学和撞击性能预测良好的渗透性，良好的口腔生物利用度，无毒性和致突变性为1C和1D。吡唑核在药物 - 目标搜索和结构活性关系（SAR）分析中具有高频命中的克鲁兹哌啶的吡唑 - 咪唑啉衍生物的分析显示，当氯原子插入苯环的Meta-possions中时，促进活性。另外，我们发现，化合物（1C和1D）的证据表明，两种化合物（1C和1D）有可能与CruziPain的活性位点相互作用，并且还抑制T.Cruzi的半胱氨酸蛋白酶活性。统称，这里提出的数据显示了吡唑衍生物，其具有进一步优化在Chagas疾病的治疗中的进一步优化。 （c）2019年Elsevier Masson SAS。版权所有。

著录项

  • 来源
  • 作者

    Monteiro M. E.; Lechuga G.; Lara L. S.; Souto B. A.; Vigano M. G.; Bourguignon S. C.; Calvet C. M.; Oliveira F. O. R. Jr.; Alves C. R.; Souza-Silva F.; Santos M. S.; Pereira M. C. S.;

  • 作者单位

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Univ Fed Itajuba Inst Fis &

    Quim Lab Sintese Organ IABSINTO Ave BPS 1303 Pinheirinho BR;

    Univ Fed Itajuba Inst Fis &

    Quim Lab Sintese Organ IABSINTO Ave BPS 1303 Pinheirinho BR;

    Univ Fed Fluminense Dept Biol Celular &

    Mol Lab Interacao Celular &

    Mol Rua Outeiro Sao Joao;

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Inst Oswald Cruz FIOCRUZ Lab Biol Mol &

    Doencas Endem Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Inst Oswald Cruz FIOCRUZ Lab Biol Mol &

    Doencas Endem Av Brasil 4365 Manguinhos BR-21040900 Rio;

    Univ Fed Itajuba Inst Fis &

    Quim Lab Sintese Organ IABSINTO Ave BPS 1303 Pinheirinho BR;

    Inst Oswaldo Cruz Lab Ultraestrutura Celular FIOCRUZ Av Brasil 4365 Manguinhos BR-21040900 Rio;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Chagas disease; Trypanosoma cruzi; Chemotherapy; Pyrazolederivatives; Cruzipain inhibitor; SAR analysis;

    机译：Chagas疾病;锥虫瘤Cruzi;化疗;吡唑酮;Cruzipain抑制剂;SAR分析;

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