一项发散性的构效关系研究使得一种强效5-HT2c抑制剂优化为一种有前景的抗疟骨架。
A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold.
作者信息
Calderón Félix, Vidal-Mas Jaume, Burrows Jeremy, de la Rosa Juan Carlos, Jiménez-Díaz María Belén, Mulet Teresa, Prats Sara, Solana Jorge, Witty Michael, Gamo Francisco Javier, Fernández Esther
机构信息
Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
Medicines for Malaria Venture (MMV) , 20, route de Pré-Bois-PO Box 1826, 1215 Geneva 15, Switzerland.
出版信息
ACS Med Chem Lett. 2012 Feb 9;3(5):373-7. doi: 10.1021/ml300008j. eCollection 2012 May 10.
Abstract
From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.
摘要
从葛兰素史克公司2010年公布的13533种化学结构中，我们确定了47个用于先导优化的优质起始点。最有前景的命中化合物之一是TCMDC-139046，它是一种具有吲哚啉核心的分子，因其通过与5-羟色胺拮抗剂受体5-HT2相互作用而具有抗焦虑特性而闻名。抑制该靶点会使这些化合物作为抗疟药的临床开发变得复杂。在此，我们展示了该系列的抗疟活性概况以及我们在保持良好抗寄生虫效力的同时避免与该受体相互作用的努力。通过双发散构效关系分析，我们获得了一种含有吲哚啉核心的新型先导化合物。
相似文献
1
A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold.一项发散性的构效关系研究使得一种强效5-HT2c抑制剂优化为一种有前景的抗疟骨架。
ACS Med Chem Lett. 2012 Feb 9;3(5):373-7. doi: 10.1021/ml300008j. eCollection 2012 May 10.
2
Novel 2-Phenoxyanilide Congeners Derived from a Hit Structure of the TCAMS: Synthesis and Evaluation of Their in Vitro Activity against Plasmodium falciparum.源自三嗪类抗疟化合物筛选命中结构的新型2-苯氧基苯胺类似物：其对恶性疟原虫体外活性的合成与评价
Molecules. 2016 Feb 17;21(2):223. doi: 10.3390/molecules21020223.
3
An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.疟疾药物研发中的开放式创新邀请：来自TCAMS的47个优质起点
ACS Med Chem Lett. 2011 Aug 3;2(10):741-6. doi: 10.1021/ml200135p. eCollection 2011 Oct 13.
4
Evaluation of aminohydantoins as a novel class of antimalarial agents.氨基乙内酰脲作为新型抗疟药的评估
ACS Med Chem Lett. 2013 Dec 6;5(1):89-93. doi: 10.1021/ml400412x. eCollection 2014 Jan 9.
5
Case Study of Small Molecules As Antimalarials: 2-Amino-1-phenylethanol (APE) Derivatives.小分子抗疟药的案例研究：2-氨基-1-苯乙醇（APE）衍生物
ACS Med Chem Lett. 2014 Mar 26;5(6):657-61. doi: 10.1021/ml500015r. eCollection 2014 Jun 12.
6
Identification of Novel 1--Substituted Aporphine Analogues as Potent 5-HT Receptor Agonists.鉴定新型 1--取代阿朴啡类似物为强效 5-HT 受体激动剂。
ACS Chem Neurosci. 2020 Feb 19;11(4):549-559. doi: 10.1021/acschemneuro.9b00563. Epub 2020 Feb 4.
7
Extracting SAR Information from a Large Collection of Anti-Malarial Screening Hits by NSG-SPT Analysis.通过NSG-SPT分析从大量抗疟筛选命中物中提取SAR信息。
ACS Med Chem Lett. 2011 Jan 5;2(3):201-6. doi: 10.1021/ml100240z. eCollection 2011 Mar 10.
8
Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS).环丙基甲酰胺：源自特雷斯坎托斯抗疟药库（TCAMS）的新型口服抗疟药系列。
ACS Med Chem Lett. 2011 Aug 29;2(11):840-4. doi: 10.1021/ml2001517. eCollection 2011 Nov 10.
9
A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery.一组具有阻断恶性疟原虫传播潜力的新化学起始点，用于抗疟药物发现。
PLoS One. 2015 Aug 28;10(8):e0135139. doi: 10.1371/journal.pone.0135139. eCollection 2015.
10
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.开源药物发现：源自特雷斯坎托斯芳基吡咯的高效抗疟化合物。
ACS Cent Sci. 2016 Oct 26;2(10):687-701. doi: 10.1021/acscentsci.6b00086. Epub 2016 Sep 14.
引用本文的文献
1
Unravelling the mode of action of the Tres Cantos Antimalarial Set (TCAMS): investigating the mechanism of potent antimalarial compounds potentially targeting the human serotonin receptor.解析三坎托斯抗疟药组（TCAMS）的作用模式：研究可能靶向人类血清素受体的强效抗疟化合物的作用机制。
Malar J. 2025 Feb 14;24(1):45. doi: 10.1186/s12936-025-05271-3.
2
Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities.疟疾感染中的激素：对疾病严重程度、宿主生理和治疗机会的影响。
Biosci Rep. 2024 Nov 27;44(11). doi: 10.1042/BSR20240482.
3
Fueling Open Innovation for Malaria Transmission-Blocking Drugs: Hundreds of Molecules Targeting Early Parasite Mosquito Stages.为疟疾传播阻断药物推动开放式创新：数百种针对疟原虫早期蚊子阶段的分子。
Front Microbiol. 2019 Sep 13;10:2134. doi: 10.3389/fmicb.2019.02134. eCollection 2019.
4
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.开源药物发现：源自特雷斯坎托斯芳基吡咯的高效抗疟化合物。
ACS Cent Sci. 2016 Oct 26;2(10):687-701. doi: 10.1021/acscentsci.6b00086. Epub 2016 Sep 14.
5
New insight-guided approaches to detect, cure, prevent and eliminate malaria.用于检测、治愈、预防和消除疟疾的新的基于深入了解的方法。
Protoplasma. 2015 May;252(3):717-53. doi: 10.1007/s00709-014-0697-x. Epub 2014 Oct 17.
6
Case Study of Small Molecules As Antimalarials: 2-Amino-1-phenylethanol (APE) Derivatives.小分子抗疟药的案例研究：2-氨基-1-苯乙醇（APE）衍生物
ACS Med Chem Lett. 2014 Mar 26;5(6):657-61. doi: 10.1021/ml500015r. eCollection 2014 Jun 12.
7
Antimalarial drug discovery - approaches and progress towards new medicines.抗疟药物发现——新药研发的方法和进展。
Nat Rev Microbiol. 2013 Dec;11(12):849-62. doi: 10.1038/nrmicro3138. Epub 2013 Nov 11.
8
A new in vivo screening paradigm to accelerate antimalarial drug discovery.一种新的体内筛选范式，加速抗疟药物发现。
PLoS One. 2013 Jun 25;8(6):e66967. doi: 10.1371/journal.pone.0066967. Print 2013.
9
Recent advances in malaria drug discovery.疟疾药物发现的最新进展。
Bioorg Med Chem Lett. 2013 May 15;23(10):2829-43. doi: 10.1016/j.bmcl.2013.03.067. Epub 2013 Mar 27.
本文引用的文献
1
Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS).环丙基甲酰胺：源自特雷斯坎托斯抗疟药库（TCAMS）的新型口服抗疟药系列。
ACS Med Chem Lett. 2011 Aug 29;2(11):840-4. doi: 10.1021/ml2001517. eCollection 2011 Nov 10.
2
An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS.疟疾药物研发中的开放式创新邀请：来自TCAMS的47个优质起点
ACS Med Chem Lett. 2011 Aug 3;2(10):741-6. doi: 10.1021/ml200135p. eCollection 2011 Oct 13.
3
Cyclopropyl carboxamides, a chemically novel class of antimalarial agents identified in a phenotypic screen.环丙基羧酰胺类，一种在表型筛选中发现的具有化学新颖性的抗疟药物类别。
Antimicrob Agents Chemother. 2011 Dec;55(12):5740-5. doi: 10.1128/AAC.05188-11. Epub 2011 Oct 3.
4
Challenges in antimalarial drug discovery.抗疟药物研发的挑战。
Future Med Chem. 2011 Sep;3(11):1401-12. doi: 10.4155/fmc.11.91.
5
Chemical genetics of Plasmodium falciparum.恶性疟原虫的化学遗传学
Nature. 2010 May 20;465(7296):311-5. doi: 10.1038/nature09099.
6
Thousands of chemical starting points for antimalarial lead identification.数以千计的抗疟药物先导化合物化学起始点。
Nature. 2010 May 20;465(7296):305-10. doi: 10.1038/nature09107.
7
In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.计算机模拟活性谱分析揭示了在高通量筛选中发现的抗疟药物的作用机制。
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9059-64. doi: 10.1073/pnas.0802982105. Epub 2008 Jun 25.
8
Drugging the Plasmodium kinome: the benefits of academia-industry synergy.靶向疟原虫激酶组：学术界与产业界协同合作的益处。
Trends Pharmacol Sci. 2008 May;29(5):241-9. doi: 10.1016/j.tips.2008.02.005. Epub 2008 Apr 18.
9
Public - private 'partnerships' in health - a global call to action.医疗卫生领域的公私“伙伴关系”——全球行动呼吁。
Health Res Policy Syst. 2004 Jul 28;2(1):5. doi: 10.1186/1478-4505-2-5.
10
Molecular basis for atovaquone binding to the cytochrome bc1 complex.阿托伐醌与细胞色素bc1复合物结合的分子基础。
J Biol Chem. 2003 Aug 15;278(33):31312-8. doi: 10.1074/jbc.M304042200. Epub 2003 Jun 5.
Zotero 插件