• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

二芳基硫醚衍生物对婴儿利什曼原虫锥虫硫醇还原酶的抑制作用。

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.

作者信息

Saccoliti Francesco, Angiulli Gabriella, Pupo Giovanni, Pescatori Luca, Madia Valentina Noemi, Messore Antonella, Colotti Gianni, Fiorillo Annarita, Scipione Luigi, Gramiccia Marina, Di Muccio Trentina, Di Santo Roberto, Costi Roberta, Ilari Andrea

机构信息

a Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco , "Sapienza" Università di Roma , Roma , Italia.

b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.

出版信息

J Enzyme Inhib Med Chem. 2017 Dec;32(1):304-310. doi: 10.1080/14756366.2016.1250755.

DOI:10.1080/14756366.2016.1250755
PMID:28098499
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6010130/
Abstract

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC=29.43 µM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (K 0.25 ± 0.18 µM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.

摘要

本文介绍的这项研究旨在鉴定一类新型的抗利什曼原虫化合物，利什曼原虫是利什曼病的病原体。为此，我们对内部化合物库中的硫醚衍生物进行了全细胞筛选试验，以确定它们对利什曼原虫的体外活性。其中，化合物RDS 777（6-(仲丁氧基)-2-((3-氯苯基)硫代)嘧啶-4-胺）取得了有前景的结果（IC = 29.43 μM），它能够通过高效抑制锥虫硫醇还原酶（TR）（K = 0.25 ± 0.18 μM）来损害寄生虫抵御活性氧的机制。婴儿利什曼原虫TR与RDS 777复合物的X射线结构揭示了该化合物的作用机制，它与催化位点结合，并与参与催化作用的残基（即Glu466'、Cys57和Cys52）形成氢键，从而抑制锥虫硫醇的结合并避免其还原。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/94f1c43a5f07/IENZ_A_1250755_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/d79b346f20ce/IENZ_A_1250755_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/0aa33c55f413/IENZ_A_1250755_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/51e181b93736/IENZ_A_1250755_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/09eaf2cae1f0/IENZ_A_1250755_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/7f65ba1b1b93/IENZ_A_1250755_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/94f1c43a5f07/IENZ_A_1250755_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/d79b346f20ce/IENZ_A_1250755_SCH0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/0aa33c55f413/IENZ_A_1250755_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/51e181b93736/IENZ_A_1250755_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/09eaf2cae1f0/IENZ_A_1250755_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/7f65ba1b1b93/IENZ_A_1250755_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2ba/6010130/94f1c43a5f07/IENZ_A_1250755_F0005_C.jpg

相似文献

1
Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.二芳基硫醚衍生物对婴儿利什曼原虫锥虫硫醇还原酶的抑制作用。
J Enzyme Inhib Med Chem. 2017 Dec;32(1):304-310. doi: 10.1080/14756366.2016.1250755.
2
Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism.基于结构的方法鉴定新型抗利什曼原虫二芳基硫化物化合物，针对的是硫醇代谢。
Amino Acids. 2020 Feb;52(2):247-259. doi: 10.1007/s00726-019-02731-4. Epub 2019 Apr 29.
3
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.一种含金药物靶向寄生虫多胺代谢：婴儿利什曼原虫硫氧还蛋白还原酶与金诺芬复合物的 X 射线结构揭示了酶抑制的双重机制。
Amino Acids. 2012 Feb;42(2-3):803-11. doi: 10.1007/s00726-011-0997-9. Epub 2011 Aug 11.
4
Molecular basis of antimony treatment in leishmaniasis.利什曼病中锑治疗的分子基础。
J Med Chem. 2009 Apr 23;52(8):2603-12. doi: 10.1021/jm900185q.
5
Inhibition of Leishmania infantum trypanothione reductase by azole-based compounds: a comparative analysis with its physiological substrate by X-ray crystallography.基于唑类化合物对利什曼原虫硫氧还蛋白还原酶的抑制作用：X 射线晶体学与生理底物的比较分析。
ChemMedChem. 2013 Jul;8(7):1175-83. doi: 10.1002/cmdc.201300176. Epub 2013 Jun 3.
6
Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum.对婴儿利什曼原虫硫氧还蛋白还原酶的选定三环和醌衍生物的分子对接研究。
J Comput Chem. 2010 Oct;31(13):2463-75. doi: 10.1002/jcc.21538.
7
Leishmania infantum trypanothione reductase is a promiscuous enzyme carrying an NADPH:O2 oxidoreductase activity shared by glutathione reductase.婴儿利什曼原虫的锥虫硫醇还原酶是一种具有混杂活性的酶，它具有谷胱甘肽还原酶所共有的NADPH:O2氧化还原酶活性。
Biochim Biophys Acta. 2015 Sep;1850(9):1891-7. doi: 10.1016/j.bbagen.2015.05.022. Epub 2015 May 29.
8
Modeled structure of trypanothione reductase of Leishmania infantum.
BMB Rep. 2008 Jun 30;41(6):444-7. doi: 10.5483/bmbrep.2008.41.6.444.
9
Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide.新型锥虫硫醇还原酶抑制剂——季铵芳基烷基铵2-氨基-4-氯苯基苯硫醚及其N-酰基衍生物的抗锥虫、抗利什曼原虫和抗疟活性
J Med Chem. 2005 Dec 15;48(25):8087-97. doi: 10.1021/jm050819t.
10
Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening.从高通量筛选中鉴定和结合新型利什曼原虫硫氧还蛋白还原酶抑制剂。
PLoS Negl Trop Dis. 2018 Nov 26;12(11):e0006969. doi: 10.1371/journal.pntd.0006969. eCollection 2018 Nov.

引用本文的文献

1
Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.靶向 trypanothione 合成酶和 trypanothione 还原酶：开发用于治疗锥虫病的通用抑制剂
Pharmaceuticals (Basel). 2025 Aug 11;18(8):1182. doi: 10.3390/ph18081182.
2
Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy.揭示抗原生动物药物的作用机制：光亲和标记策略综述
Pharmaceuticals (Basel). 2024 Dec 28;18(1):28. doi: 10.3390/ph18010028.
3
In vitro and in silico approaches manifest the anti-leishmanial activity of wild edible mushroom .

本文引用的文献

1
Targeting polyamine metabolism for finding new drugs against leishmaniasis: a review.靶向多胺代谢以寻找抗利什曼病的新药：综述
Mini Rev Med Chem. 2015;15(3):243-52. doi: 10.2174/138955751503150312141044.
2
Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation.银纳米颗粒对锥虫硫醇还原酶活性及婴儿利什曼原虫增殖的抑制作用。
ACS Med Chem Lett. 2010 Dec 29;2(3):230-3. doi: 10.1021/ml1002629. eCollection 2011 Mar 10.
3
Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs.
体外和计算机模拟方法表明野生食用蘑菇具有抗利什曼原虫活性。
In Silico Pharmacol. 2024 Dec 24;13(1):6. doi: 10.1007/s40203-024-00287-0. eCollection 2025.
4
Targeting Trypanothione Metabolism in Trypanosomatids.靶向原虫的硫醇代谢。
Molecules. 2024 May 9;29(10):2214. doi: 10.3390/molecules29102214.
5
Miconazole-like Scaffold is a Promising Lead for -Specific CYP51 Inhibitors.咪康唑类支架是一种有前途的靶向特异性 CYP51 抑制剂先导化合物。
J Med Chem. 2023 Dec 28;66(24):17059-17073. doi: 10.1021/acs.jmedchem.3c01898. Epub 2023 Dec 12.
6
Antileishmanial Activity of S. Leiva & Meerow (Amaryllidaceae) Collected in Peru.在秘鲁采集的利瓦氏水仙与米罗水仙（石蒜科）的抗利什曼原虫活性
Plants (Basel). 2023 Jan 10;12(2):322. doi: 10.3390/plants12020322.
7
Selene-Ethylenelacticamides and -Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents.作为广谱杀利什曼原虫剂的月桂烯乙酰胺和芳基丙酰胺
Pathogens. 2023 Jan 13;12(1):136. doi: 10.3390/pathogens12010136.
8
Inhibition of Trypanothione Reductase by New Aminopropanone Derivatives Interacting with the NADPH Binding Site.新型氨基丙酮衍生物与 NADPH 结合位点相互作用抑制还原型谷胱甘肽还原酶。
Molecules. 2023 Jan 1;28(1):338. doi: 10.3390/molecules28010338.
9
Metabolic Pathways of Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates.寄生虫的代谢途径：相关药物靶点和有效候选药物的来源
Pharmaceutics. 2022 Jul 30;14(8):1590. doi: 10.3390/pharmaceutics14081590.
10
Ethnomedicinal, Phytochemical and Pharmacological Investigations of (Hochst.) Codd (Lamiaceae).对（霍赫斯特）科德（唇形科）的民族药用、植物化学和药理学研究。
Front Pharmacol. 2022 Jun 2;13:896078. doi: 10.3389/fphar.2022.896078. eCollection 2022.
结构洞察三价氮循环途径的酶：抗利什曼原虫药物的作用靶点。
Future Med Chem. 2013 Oct;5(15):1861-75. doi: 10.4155/fmc.13.146.
4
Inhibition of Leishmania infantum trypanothione reductase by azole-based compounds: a comparative analysis with its physiological substrate by X-ray crystallography.基于唑类化合物对利什曼原虫硫氧还蛋白还原酶的抑制作用：X 射线晶体学与生理底物的比较分析。
ChemMedChem. 2013 Jul;8(7):1175-83. doi: 10.1002/cmdc.201300176. Epub 2013 Jun 3.
5
The crystal structures of the tryparedoxin-tryparedoxin peroxidase couple unveil the structural determinants of Leishmania detoxification pathway.该半胱氨酸过氧化物酶还原酶体系的晶体结构揭示了利什曼原虫解毒途径的结构决定因素。
PLoS Negl Trop Dis. 2012;6(8):e1781. doi: 10.1371/journal.pntd.0001781. Epub 2012 Aug 21.
6
Facilities for macromolecular crystallography at the Helmholtz-Zentrum Berlin.柏林亥姆霍兹研究中心的大分子晶体学设施。
J Synchrotron Radiat. 2012 May;19(Pt 3):442-9. doi: 10.1107/S0909049512006395. Epub 2012 Mar 20.
7
Neglected tropical diseases of the Middle East and North Africa: review of their prevalence, distribution, and opportunities for control.中东和北非的被忽视热带病：流行情况、分布及控制机会综述。
PLoS Negl Trop Dis. 2012;6(2):e1475. doi: 10.1371/journal.pntd.0001475. Epub 2012 Feb 28.
8
Design, synthesis and biological evaluation of Trypanosoma brucei trypanothione synthetase inhibitors.设计、合成及生物评价抗布氏锥虫硫醇合成酶抑制剂。
ChemMedChem. 2012 Jan 2;7(1):95-106. doi: 10.1002/cmdc.201100420. Epub 2011 Dec 8.
9
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.一种含金药物靶向寄生虫多胺代谢：婴儿利什曼原虫硫氧还蛋白还原酶与金诺芬复合物的 X 射线结构揭示了酶抑制的双重机制。
Amino Acids. 2012 Feb;42(2-3):803-11. doi: 10.1007/s00726-011-0997-9. Epub 2011 Aug 11.
10
XDS.XDS.（这个词如果没有更多背景信息，很难准确翻译出更有意义的内容，直接保留原文是一种处理方式，或者音译为“克斯达斯”之类，但感觉都不太符合常规翻译场景，你可以补充更多关于这个词的信息以便我更准确翻译 ）
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32. doi: 10.1107/S0907444909047337. Epub 2010 Jan 22.