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Bioorg Med Chem. 2010 Apr 1;18(7):2566-74. doi: 10.1016/j.bmc.2010.02.034. Epub 2010 Mar 1.

Assessing the trypanocidal potential of natural and semi-synthetic diketopiperazines from two deep water marine-derived fungi.

Author information

1
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA.

Abstract

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 1microg/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 (IC(50)=0.002-40microM), 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 20microM. A preliminary activity pattern is described and analyzed.

PMID:
20303767
PMCID:
PMC2893881
DOI:
10.1016/j.bmc.2010.02.034
[Indexed for MEDLINE]
Free PMC Article

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