In Vitro and in Vivo Activity of Multitarget Inhibitors against Trypanosoma brucei

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• 作者：Gyongseon Yang ; Wei Zhu ; Yang Wang ; Guozhong Huang ; Soo Young Byun ; Gahee Choi ; Kai Li ; Zhuoli Huang ; Roberto Docampo ; Eric Oldfield ; Joo Hwan No
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：August 14, 2015
• 年：2015
• 卷：1
• 期：8
• 页码：388-398
• 全文大小：603K
• ISSN：2373-8227

文摘

We tested a series of amidine and related compounds against Trypanosoma brucei. The most active compound was a biphenyldiamidine that had an EC₅₀ of 7.7 nM against bloodstream-form parasites. There was little toxicity against two human cell lines with CC₅₀ > 100 μM. There was also good in vivo activity in a mouse model of infection with 100% survival at 3 mg/kg i.p. The most potent lead blocked replication of kinetoplast DNA (k-DNA), but not nuclear DNA, in the parasite. Some compounds also inhibited the enzyme farnesyl diphosphate synthase (FPPS), and some were uncouplers of oxidative phosphorylation. We developed a computational model for T. brucei cell growth inhibition (R² = 0.76) using DNA ΔT_m values for inhibitor binding combined with T. brucei FPPS IC₅₀ values. Overall, the results suggest that it may be possible to develop multitarget drug leads against T. brucei that act by inhibiting both k-DNA replication and isoprenoid biosynthesis.