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

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 1 μg/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 μM), 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 μM. A preliminary activity pattern is described and analyzed.

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

“…Compound 7 was identified as gliotoxin by comparing the data with the literature values [24,25] (Supplementary Figures S46–S48). The NMR spectra data of compound 8 closely resembled those of 7 , except for one additional 1 H resonance signal of the acetyl group.…”

Bioprospection of Cytotoxic Compounds in Fungal Strains Recovered from Sediments of the Brazilian Coast

“…This is the first report on isolation of 2 and 3 from a natural source. Compound 2 has been previously reported as a reaction product of acetylgliotoxin (5) [21] and 1 [22], while compound 3 has been obtained as a reaction product of 5 with a large excess of elemental sulfur [24].…”

Metabolites from endophytic Aspergillus fumigatus and their in vitro effect against the causal agent of tuberculosis

“…fumigatusis an etiologic agent, responsible for fungal infections in immunosuppressed patients (Latagé, 1999), it is also known to produce a vast plethora of bioactives (Magotra et al 2017), somewith significant antimicrobial activity in initial bioactivity screens. Fractions from the extract were able to inhibit the growth of Staphylococcus aureus, including the methicillin-resistant strain, and Mycobacterium tuberculosis H37Ra (Flewelling et al 2015).The potential of A. fumigatus as a producer of secondary metabolites has already been shown in other studies, where it produced antibiotics (Waksman and Geiger 1944;Furtado et al 2005), antifungals (Mukhopadhyay et al 1987;Schulz et al 2002;Liu et al 2004), and substances with anti-acetyl-CoA activity (Tomoda et al 1994), antitumor activity (Cui et al 1995) and antitrypanosomal activity (Watts et al 2010).…”