期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 4, 页码 1509-1522出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01740
关键词
-
资金
- Spanish Ministerio de Economia y Competitividad [SAF201S-66690-R]
- TET-fund studentship from the government of Nigeria
- Mac Robertson Travel Scholarship from the College of Medical, Veterinary and Life Sciences of the University of Glasgow
- Grants-in-Aid for Scientific Research [26253025, 26440027] Funding Source: KAKEN
We investigated a chemical strategy to boost the trypanocidal activity of 2,4-dihydroxybenzoic acid (2,4-DHBA)- and salicylhydroxamic acid (SHAM)-based trypanocides with triphenylphosphonium and quinolinium lipophilic cations (LC). Three series of LC conjugates were synthesized that were active in the submicromolar (5a-d and 10d-f to low nanomolar (6a-f) range against wild-type and multidrug resistant strains of African trypanosomes (Trypanosoma brucei brucei and T. congolense). This represented an improvement in trypanocidal potency of at least 200-fold, and up to >10 000-fold, compared with that of non-LC-coupled parent compounds 2,4-DHBA and SHAM. Selectivity over human cells was >500 and reached >23 000 for 6e. Mechanistic studies showed that 6e did not inhibit the cell cycle but affected parasite respiration in a dose-dependent manner. Inhibition of trypanosome alternative oxidase and the mitochondrial membrane potential was also studied for selected compounds. We conclude that effective mitochondrial targeting greatly potentiated the activity of these series of compounds.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据