Redox-active dinitrodiphenylthioethers against Leishmania
详细信息 查看全文
- 作者：Dawn A. Delfí ; n ; Rachel E. Morgan ; Xiaohua Zhu ; Karl A. Werbovetz
- 关键词：Leishmania ; Aromatic nitro groups ; Reactive oxygen species ; Mitochondrial membrane potential
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2009
- 出版时间：15 January 2009
- 年：2009
- 卷：17
- 期：2
- 页码：820-829
- 全文大小：423 K
文摘
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 Maybridge 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.