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

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 7; pp. 2566 - 2574
• Main Authors: Watts, Katharine R., Ratnam, Joseline, Ang, Kean-Hooi, Tenney, Karen, Compton, Jennifer E., McKerrow, James, Crews, Phillip
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2010; Elsevier
• Subjects: Acetylation; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Aspergillus fumigatus - chemistry; Biological and medical sciences; Cysteine Endopeptidases - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Diketopiperazines - chemistry; Diketopiperazines - isolation & purification; Diketopiperazines - pharmacology; Drug Evaluation, Preclinical; Fungi - chemistry; General pharmacology; Geologic Sediments - chemistry; Humans; Indicators and Reagents; Jurkat Cells; Magnetic Resonance Spectroscopy; Marine natural products; Marine-derived fungi; Medical sciences; Methylation; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Piperazines - chemistry; Rhodesain; Spiro Compounds - chemistry; Structure-Activity Relationship; TbCatB; Trypanocidal Agents - chemistry; Trypanocidal Agents - isolation & purification; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei; Marine-derived fungi; TbCatB; Marine natural products; Rhodesain; Pentacyclic compound; Nitrogen heterocycle; Cysteine endopeptidases; Organic sulfide; Fungi; Marine environment; Antiprotozoal agent; Organic disulfide; Cathepsin B; Chemical synthesis; Hemisynthesis; Kinetoplastida; Protozoa; Sulfur nitrogen heterocycle; Enzyme; Natural compound; Deep water; Biological activity; Spiran; Peptidases; Screening; Hydrolases; Parasiticide; Isolation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.02.034

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 1μg/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=0.002–40μM), 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 20μM. A preliminary activity pattern is described and analyzed.