期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 7, 页码 2566-2574出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.02.034
关键词
Marine-derived fungi; Trypanosoma brucei; Rhodesain; TbCatB; Marine natural products
资金
- Sandler Family Foundation
- California Institute for Quantitative Biosciences [QB3]
- NSF [CHE-0342912]
- NIH [S10-RR19918, S10-RR20939]
- NATIONAL CANCER INSTITUTE [U19CA052955, R01CA047135] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR020939, S10RR019918] Funding Source: NIH RePORTER
Human African trypanosomiasis (HAT, commonly known as African sleeping sickness) is categorized as a neglected disease, as it afflicts >50,000 people annually in sub-saharan Africa, and there are few formal programs in the world focused on drug discovery approaches for this disease. In this study, we examined the crude extracts of two fungal strains (Aspergillus fumigatus and Nectria inventa) isolated from deep water sediment which provided >99% growth inhibition at 1 mu g/mL of Trypanosoma brucei, the causative parasite of HAT. A collection of fifteen natural products was supplemented with six semi-synthetic derivatives and one commercially available compound. Twelve of the compounds, each containing a diketopiperazine core, showed excellent activity against T. brucei (IC50 = 0.002-40 mu M), with selectivity over mammalian cells as great as 20-fold. The trypanocidal diketopiperazines were also tested against two cysteine protease targets Rhodesain and TbCatB, where five compounds showed inhibition activity at concentrations less than 20 mu M. A preliminary activity pattern is described and analyzed. (C) 2010 Elsevier Ltd. All rights reserved.
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