Redox-active dinitrodiphenylthioethers against Leishmania: Synthesis, structure-activity relationships and mechanism of action studies
Redox-active dinitrodiphenylthioethers against Leishmania: Synthesis, structure-activity relationships and mechanism of action studies
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DOI：
10.1016/j.bmc.2008.11.031
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发表时间：
2009-01-15
影响因子：
3.5
通讯作者：
Werbovetz, Karl A.
中科院分区：
文献类型：
--
作者：
Delfin, Dawn A.;Morgan, Rachel E.;Werbovetz, Karl A.
BTB 06237(2-[(2，4-dichloro-5-methylphenyl)sulfanyl]-1，3-dinitro-5-(trifluoromethyl)benzene)，是先前通过定量构效关系药效团开发和May-Bridge数据库的虚拟筛选而确定的化合物，具有强大的选择性抗利什曼原虫活性。在本研究中，合成了几个BTB 06237类似物，并分析了它们对无性利什曼原虫的活性、降低巨噬细胞内寄生虫血症水平的能力以及它们在杜氏利什曼原虫前鞭毛体中产生活性氧(ROS)的能力。研究发现，在先导化合物中2，4-二氯-5-甲基苯基所在的位置必须有一个芳香环，但改变官能团一般对抗利什曼效力影响不大。1，3-二硝基-5-(三氟甲基)苯环的改变对抗寄生虫活性的影响较大，需要两个芳香硝基和第三个吸电子基团。这种结构要求与氧化还原电位、在寄生虫中产生ROS的能力以及线粒体膜电位的耗散相对应。最后，我们利用收集的数据设计了一种新的抗利什曼化合物，该化合物具有很强的体外活性，并改善了作为抗利什曼候选药物的性能。(C)2008爱思唯尔有限公司。保留所有权利。
BTB 06237 (2-[(2,4-dichloro-5-methylphenyl)sulfanyl]-1,3-dinitro-5-(trifluoromethyl)benzene), a compound previously identified through QSAR pharmacophore development and a virtual screen of the May-bridge database, possesses potent and selective activity against Leishmania parasites. In the present study, several analogs of BTB 06237 were synthesized and analyzed for activity against Leishmania axenic amastigotes, their ability to reduce the level of parasitemia in peritoneal macrophages, and their ability to generate reactive oxygen species (ROS) in L. donovani promastigotes. It was found that an aromatic ring must be present in the position occupied by the 2,4-dichloro-5-methylphenyl group in the lead compound, but changing the functional groups generally has little effect on the antileishmanial potency. Alterations to the 1,3-dinitro-5-(trifluoromethyl) benzene ring have more influence on antiparasitic activity with two aromatic nitro groups and a third electron-withdrawing group being required. This structural requirement corresponds with redox potential, the ability to generate ROS in the parasites, and dissipation of the mitochondrial membrane potential. Finally, we used this collection of data to design a new antileishmanial compound with strong activity in vitro and improved properties as an antileishmanial candidate. (C) 2008 Elsevier Ltd. All rights reserved.