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本文引用的文献

1
Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by Delta(24(25)) sterol methyl transferase inhibitors and their combinations with ketoconazole.Delta(24(25)) 甾醇甲基转移酶抑制剂及其与酮康唑联合诱导的克氏锥虫的超微结构改变。
Int J Antimicrob Agents. 1997 Feb;8(1):1-6. doi: 10.1016/s0924-8579(96)00345-7.
2
New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action.新型抗布氏锥虫氮杂甾醇：24-甾醇甲基转移酶在抑制剂作用中的角色
Antimicrob Agents Chemother. 2006 Aug;50(8):2595-601. doi: 10.1128/AAC.01508-05.
3
Antiproliferative and ultrastructural effects of BPQ-OH, a specific inhibitor of squalene synthase, on Leishmania amazonensis.角鲨烯合酶特异性抑制剂BPQ-OH对亚马逊利什曼原虫的抗增殖及超微结构效应
Exp Parasitol. 2005 Dec;111(4):230-8. doi: 10.1016/j.exppara.2005.08.006. Epub 2005 Sep 29.
4
Analogues of thiolactomycin as potential antimalarial agents.硫内酯霉素类似物作为潜在的抗疟药。
J Med Chem. 2005 Sep 22;48(19):5932-41. doi: 10.1021/jm049067d.
5
Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics.制备作为潜在抗寄生虫药物的固醇24-甲基转移酶过渡态类似物。
Bioorg Med Chem. 2005 Sep 15;13(18):5435-53. doi: 10.1016/j.bmc.2005.06.012.
6
Biphenylquinuclidines as inhibitors of squalene synthase and growth of parasitic protozoa.联苯喹核碱作为角鲨烯合酶抑制剂及对寄生原生动物生长的影响
Bioorg Med Chem. 2005 May 16;13(10):3519-29. doi: 10.1016/j.bmc.2005.02.060.
7
Novel azasterols as potential agents for treatment of leishmaniasis and trypanosomiasis.新型氮杂甾醇作为治疗利什曼病和锥虫病的潜在药物。
Antimicrob Agents Chemother. 2004 Aug;48(8):2937-50. doi: 10.1128/AAC.48.8.2937-2950.2004.
8
Effects of squalene synthase inhibitors on the growth and ultrastructure of Trypanosoma cruzi.角鲨烯合酶抑制剂对克氏锥虫生长和超微结构的影响。
Int J Antimicrob Agents. 2004 Jul;24(1):72-8. doi: 10.1016/j.ijantimicag.2003.12.009.
9
In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi.两种新型口服活性角鲨烯合酶抑制剂E5700和ER-119884对克氏锥虫的体外和体内活性
Antimicrob Agents Chemother. 2004 Jul;48(7):2379-87. doi: 10.1128/AAC.48.7.2379-2387.2004.
10
Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi.氮杂甾醇作为利什曼原虫属和克氏锥虫中甾醇24-甲基转移酶的抑制剂。
J Med Chem. 2003 Oct 23;46(22):4714-27. doi: 10.1021/jm021114j.

奎宁环衍生物作为潜在的抗寄生虫药物。

Quinuclidine derivatives as potential antiparasitics.

作者信息

Cammerer Simon B, Jimenez Carmen, Jones Simon, Gros Ludovic, Lorente Silvia Orenes, Rodrigues Carlos, Rodrigues Juliany C F, Caldera Aura, Ruiz Perez Luis Miguel, da Souza Wanderley, Kaiser Marcel, Brun Reto, Urbina Julio A, Gonzalez Pacanowska Dolores, Gilbert Ian H

机构信息

Welsh School of Pharmacy, Cardiff University, United Kingdom.

出版信息

Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61. doi: 10.1128/AAC.00205-07. Epub 2007 Aug 20.

DOI:10.1128/AAC.00205-07
PMID:17709461
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2151445/
Abstract

There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.

摘要

迫切需要开发用于治疗诸如恰加斯病和利什曼病等热带寄生虫病的新药。在引发这些疾病的生物体中，一个潜在的药物靶点是甾醇生物合成。本文描述了奎宁环衍生物的设计与合成，这些衍生物作为甾醇生物合成中关键酶——角鲨烯合酶（SQS）的潜在抑制剂。发现了许多在亚微摩尔浓度下是重组硕大利什曼原虫SQS抑制剂的化合物。其中一些化合物对寄生虫酶具有选择性，而非对同源的人类酶具有选择性。这些化合物抑制利什曼原虫寄生虫的生长和甾醇生物合成。此外，我们还鉴定出了其他抑制布氏锥虫（人类非洲锥虫病的病原体）和恶性疟原虫（疟疾的病原体之一）生长的奎宁环衍生物，但作用方式未知。