Quinuclidine derivatives as potential antiparasiticsdel
Quinuclidine derivatives as potential antiparasiticsdel
复制标题
DOI：
10.1128/aac.00205-07
复制
发表时间：
2007-11-01
影响因子：
4.9
通讯作者：
Gilbert, Ian H.
中科院分区：
文献类型：
--
作者：
Cammerer, Simon B.;Jimenez, Carmen;Gilbert, Ian H.
迫切需要开发治疗南美锥虫病和利什曼病等热带寄生虫病的新药。引起这些疾病的生物体中的一个潜在药物靶点是固醇生物合成。本文介绍了奎宁环衍生物的设计和合成，作为潜在的抑制剂的甾醇生物合成的关键酶，角鲨烯合酶（SQS）。发现了许多化合物在亚微摩尔浓度下是重组硕大利什曼原虫SQS的抑制剂。这些化合物中的一些也对寄生虫酶而不是同源的人类酶具有选择性。这些化合物抑制利什曼原虫的生长和甾醇的生物合成。此外，我们鉴定了抑制布氏锥虫（人类非洲锥虫病的病原体）和恶性疟原虫（疟疾的病原体）生长的其他奎宁环衍生物，但是通过未知的作用模式。
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.